US 20070021589A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2007/0021589 A1 Collier et al. (43) Pub. Date: Jan. 25, 2007

(54) OBESITY-RELATED (52) U.S. Cl...... 530/350; 514/12: 435/69.1; (76) Inventors: Greg Collier, Ocean Grove (AU); Ken 435/320.1; 435/325; 536/23.5 Walder, Ocean Grove (AU); David Segal, Ocean Grove (AU); Victoria C. Foletta, Ocean Grove (AU) (57) ABSTRACT Correspondence Address: SCULLY, SCOTT, MURPHY & PRESSER The present invention relates generally to a nucleic acid 4OO GARDEN CITY PLAZA molecule which is expressed in at least red gastrocnemius SUTE 3OO muscle or its equivalent under particular physiological con GARDEN CITY, NY 11530 (US) ditions. It is proposed that the nucleic acid molecule is (21) Appl. No.: 10/541,998 differentially expressed under differing conditions of healthy state, myopathy, obesity, anorexia, weight maintenance, (22) PCT Filed: Jan. 13, 2004 diabetes, disorders associated with mitochondrial dysfunc (86). PCT No.: PCT/AUO4/OOO43 tion, genetic disorders, cancer, heart disease, inflammation, S 371(c)(1), disorders associated with the immune system, infertility, (2), (4) Date: Jan. 17, 2006 disease associated with the brain and/or metabolic energy levels. The subject nucleic acid molecule and/or its expres (30) Foreign Application Priority Data sion product is proposed to be used in therapeutic and diagnostic protocols for conditions such as healthy state, Jan. 13, 2003 (US)...... 60439767 myopathy, obesity, anorexia, weight maintenance, diabetes, Publication Classification disorders associated with mitochondrial dysfunction, (51) Int. Cl. genetic disorders, cancer, heart disease, inflammation, dis C07K I4/705 (2007.01) orders associated with the immune system, infertility, dis A6 IK 38/17 (2007.01) ease associated with the brain and/or metabolic energy C7H 2L/04 (2006.01) levels or as targets for the design and/or identification of CI2P 2/06 (2006.01) modulators of their activity and/or function. US 2007/0021589 A1 Jan. 25, 2007

OBESTY-RELATED GENES 0008. In Australia, the recent AusLiab study estimated that 7.5 million Australians (60%) aged 25 years and over BACKGROUND OF THE INVENTION were overweight or obese. Of these, 2.6 million (21%) were obese (BMI>30) (Dunstan et al., Diabetes Res. Clin. Pract. 0001) 1. Field of the Invention 57: 119-129, 2002). Similarly, the prevalence of obesity in 0002 The present invention relates generally to a nucleic the U.S. increased substantially between 1991 and 1998, acid molecule which is expressed in at least red gastrocne increasing from 12% to 18% in Americans during this period mius muscle or its equivalent under particular physiological (Mokdad et al., JAMA 282(16): 1519-1522, 1999). conditions. It is proposed that the nucleic acid molecule is 0009. The high and increasing prevalence of obesity has differentially expressed under differing conditions of healthy serious health implications for both individuals and society state, myopathy, obesity, anorexia, weight maintenance, as a whole. Obesity is a complex and heterogeneous disorder diabetes, disorders associated with mitochondrial dysfunc and has been identified as a key risk indicator of preventable tion, genetic disorders, cancer, heart disease, inflammation, morbidity and mortality as obesity increases the risk of a disorders associated with the immune system, infertility, number of other metabolic conditions including type 2 disease associated with the brain and/or metabolic energy diabetes mellitus and cardiovascular disease (Must et al., levels. The subject nucleic acid molecule and/or its expres JAMA 282(16): 1523-1529, 1999: Kopelman, Nature 404: sion product is proposed to be used in therapeutic and 635-643, 2000). Alongside obesity the prevalence of diabe diagnostic protocols for conditions such as healthy state, tes continues to increase rapidly. The AusLiab Survey esti myopathy, obesity, anorexia, weight maintenance, diabetes, mated that close to 1 million Australians aged 25 years and disorders associated with mitochondrial dysfunction, over have type 2 diabetes (Dunstan et al., 2002). This genetic disorders, cancer, heart disease, inflammation, dis represents approximately 7.5% of the population. In the orders associated with the immune system, infertility, dis U.S., the number of adults with diabetes increased by 49% ease associated with the brain and/or metabolic energy between 1991 and 2000 (Marx, Science 686-689, 2002). It levels or as targets for the design and/or identification of has been estimated that about 17 million people in the U.S. modulators of their activity and/or function. have type 2 diabetes and an equal number are thought to be pre-diabetic (Marx, 2002). In Australia, the annual costs of 0003 2. Description of the Prior Art obesity associated with diabetes and other disease conditions 0004 Bibliographic details of references provided in the has been conservatively estimated to be AUS$810 million subject specification are listed at the end of the specification. for 1992-93 (National Health and Medical Research Coun cil, Acting on Australia's weight. A strategy for the preven 0005 Reference to any prior art in this specification is tion of overweight and obesity. Canberra: National Health not, and should not be taken as, an acknowledgment or any and Medical Research Council, 1996). The direct costs of form of Suggestion that this prior art forms part of the diabetes and its complications in Australia in 1993-94 were common general knowledge in any country. estimated at S681 million, or 2.2% of total health system 0006 The increasing sophistication of recombinant DNA costs in that year (Australian Institute of Health and Welfare technology is greatly facilitating research and development (AIWH), Australia's Health, 2002, Canberra: AIWH). in the medical, veterinary and allied human and animal 0010. A genetic basis for the etiology of obesity is health fields. This is particularly the case in the investigation indicated inter alia from Studies in twins, adoption studies of the genetic bases involved in the etiology of certain and population-based analyses which suggest that genetic disease conditions. One particularly significant condition effects account for 25-80% of the variation in body weight from the stand point of morbidity and mortality is obesity in the general population (Bouchard, 1994, Supra; Kopelman and its association with type 2 diabetes (formerly non et al., Int. J. Obesity 18: 188-191, 1994; Ravussin, Metabo insulin-dependent diabetes mellitus or NIDDM) and cardio lism 44(3): 12-14, 1995). It is considered that genes deter vascular disease. mine the possible range of body weight in an individual and then the environment influences the point within this range 0007 Obesity is defined as a pathological excess of body where the individual is located at any given time (Bouchard, fat and is the result of an imbalance between energy intake 1994). However, despite numerous studies into genes and energy expenditure for a Sustained period of time. thought to be involved in the pathogenesis of obesity, there Obesity is the most common metabolic disease found in affluent societies. The prevalence of obesity in these nations have been Surprisingly few significant findings in this area. is alarmingly high, ranging from 10% to upwards of 50% in In addition, genome-wide scans in various population Some Sub-populations (Bouchard. The genetics of Obesity, groups have not produced definitive evidence of the chro Boca Raton: CRC Press, 1994). Of particular concern is the mosomal regions having a major effect on obesity. fact that the prevalence of obesity appears to be rising 0011) A number of tissues have been implicated in the consistently in affluent Societies and is now increasing pathophysiology of obesity and type 2 diabetes, and of rapidly in less prosperous nations as they become more particular interest is the muscle. Skeletal muscle is the affluent and/or adopt cultural practices similar to those in principle site of insulin-stimulated glucose disposal, more affluent countries (Zimmet, Diabetes Care 15: 232 accounting for approximately 75% of total glucose uptake. 252, 1992). The escalating rates of obesity globally have Skeletal muscle is also the major site of peripheral insulin resulted in the World Health Organisation declaring an resistance. Skeletal muscle also oxidizes free fatty acids for obesity epidemic worldwide (World Trade Organisation. fuel, to meet its energy requirements. In healthy individuals, Obesity. Preventing and managing the global epidemic. the muscle has the capacity to utilize both carbohydrate and Report of a WHO Consultation on Obesity. Geneva: World lipids for energy and to fluctuate between these fuels in Health Organisation, 1998). response to a range of signals including insulin concentra US 2007/0021589 A1 Jan. 25, 2007

tions. This metabolic flexibility is central to the role the both known genes and unknown transcripts. Using cDNA muscle plays in whole body fuel metabolism and with microarrays, comparative estimates can be obtained of the diseases such as obesity and type 2 diabetes, this flexibility level of expression of large numbers of genes (up to may be lost. 20,000 per microarray) in each sample. cDNA microarrays generally involve a large number of DNA “spots” in an SUMMARY OF THE INVENTION orderly array chemically coupled to the surface of a solid Substrate, usually but not exclusively an optically flat glass 0012 Throughout this specification, unless the context microscope slide. Fluorescently labeled cDNAs are gener requires otherwise, the word “comprise', or variations such ated from experimental and reference RNA samples and as “comprises” or “comprising, will be understood to imply then competitively hybridized to the gene chip. The experi the inclusion of a stated element or integer or group of mental and reference cDNAs are labeled with a different elements or integers but not the exclusion of any other fluorescent dye and the intensity of each fluor at each DNA element or integer or group of elements or integers. spot gives an indication of the level of that particular RNA 0013 Nucleotide and sequences are referred species in the experimental sample relative to the reference to by a sequence identifier number (SEQID NO:). The SEQ RNA. The ratio of fluorescence can be taken as a measure of ID NOs: correspond numerically to the sequence identifiers the expression level of the gene corresponding to that spot <400>1 (SEQ ID NO:1), <400>2 (SEQ ID NO:2), etc. A in the experimental sample. summary of the sequence identifiers is provided in Table 3. 0021. In a preferred embodiment, nine expressed A sequence listing is provided after the claims. A Summary sequences were identified designated herein AGT-701 SEQ of genes identified in accordance with the present invention ID NO:1), AGT-702 SEQ ID NO:2), AGT-704 SEQ ID is provided in Table 1. Gene abbreviations are provided in NO:3), AGT-705 SEQ ID NO:4), AGT-706 SEQ ID Table 2. NO:5), AGT-707 SEQ ID NO:6), AGT-708 SEQ ID 0014. In accordance with the present invention, genetic NO:7), AGT-709 SEQ ID NO:8) and AGT-710 SEQ ID sequences were sought which are expressed in at least red NO:9). The corresponding expression products are provided gastrocnemius muscle of Psanimomys obesus (Israeli Sand in non-itallicized form, i.e. AGT-701, AGT702, AGT-704, Rat) under particular physiological conditions. Novel genes AGT-705, AGT-706, AGT-707, AGT-708, AGT-709, AGT were then identified which have human and/or murine 710. equivalents or homologs. In accordance with the present invention, genes are isolated which are proposed to be 0022. A summary of the AGT genes is provided in Table associated with one or more biological functions associated 1. with disease conditions such as but not limited to healthy 0023 The present invention contemplates the use of these state, myopathy, obesity, anorexia, weight maintenance, sequences or their expression products in the manufacture of diabetes, disorders associated with mitochondrial dysfunc medicaments and diagnostic agents for a range of conditions tion, genetic disorders, cancer, heart disease, inflammation, including healthy state, myopathy, obesity, anorexia, weight disorders associated with the immune system, infertility, maintenance, diabetes, disorders associated with mitochon disease associated with the brain and/or metabolic energy drial dysfunction, genetic disorders, cancer, heart disease, levels. inflammation, disorders associated with the immune system, 0.015 Analysis of genetic material from red gastrocne infertility, disease associated with the brain and/or metabolic mius muscle tissue were used to identify candidate genetic energy levels. sequences associated with a healthy state or with physiologi 0024. The present invention provides, therefore, a nucleic cal conditions such as healthy state, myopathy, obesity, acid molecule comprising a sequence of nucleotides encod anorexia, weight maintenance, diabetes, disorders associ ing or complementary to a sequence encoding an expression ated with mitochondrial dysfunction, genetic disorders, can product or a derivative, homolog, analog or mimetic thereof cer, heart disease, inflammation, disorders associated with wherein said nucleic acid molecule or its homolog is dif the immune system, infertility, disease associated with the ferentially expressed in red gastrocnemius of P. obesus brain and/or metabolic energy levels. The Psammomys obe under fed or fasted or in exercise trained and control sus animal model comprises three groups of animals desig conditions. nated Groups A, B and C based on metabolic phenotype as follows: 0025 The present invention further provides mammalian homology of the Subject nucleic acid molecules Such as 0016 Group A: lean animals (normoglycernic; normoin human homology. Sulinemic); 0026. The present invention still further provides a 0017 Group B: obese, non-diabetic animals (normogly nucleic acid molecule comprising a nucleotide sequence cemic; hyperinsulinemic); and encoding or complementary to a sequence encoding an 0018 Group C: obese, diabetic animals (hyperglycemic: expression product or a derivative, homolog, analog or hyperinsulinemic). mimetic thereof wherein the nucleotide sequence is as 0.019 Microarray analysis was used to identify genetic substantially set forth in SEQID NO:1 or SEQID NO:2 or SEQID NO:3 or SEQID NO:4 or SEQID NO:5 or SEQID sequences in fed and fasted mammals or in exercise trained NO:6 or SEQ ID NO:7 or SEQ ID NO:8 or SEQ ID NO:9 and control mammals. Psammomys obesus was found to be or a nucleotide sequence having at least about 30% identity particularly useful for this analysis. to all or part of SEQID NO:1 or SEQ ID NO:2 or SEQ ID 0020 cl NA microarray technology provides a powerful NO:3 or SEQID NO:4 or SEQ ID NO:5 or SEQID NO:6 technical means to generate a gene expression database of or SEQID NO:7 or SEQID NO:8 or SEQID NO:9 and/or US 2007/0021589 A1 Jan. 25, 2007 is capable of hybridizing to one or more of SEQID NO:1 or 0031. The present invention is particularly directed to SEQID NO:2 or SEQID NO:3 or SEQID NO:4 or SEQID mammalian and in particular human homologs of the genes NO:5 or SEQ ID NO:6 or SEQ ID NO:7 or SEQ ID NO:8 identified in P. obesus and their use or the use of expression or SEQ ID NO:9 or their complementary forms under low products in therapy and diagnosis. stringency conditions at 42°C. and wherein the nucleic acid 0032) Another aspect of the present invention contem molecule is differentially expressed in red gastocnemius plates, therefore, a method for treating a Subject comprising tissue of P. obesus under fed or fasted or in exercise trained administering to said subject a treatment effective amount of and control conditions. AGT-701, AGT-702, AGT-704, AGT-705, AGT-706, AGT 0027. The present invention also provides an isolated 707, AGT-708, AGT-709 and/or AGT-710 or a derivative, expression product or a derivative, homolog, analog or homolog, analog or mimetic thereof or a genetic sequence mimetic thereof which expression product is encoded by a encoding same or an agonist or antagonist of AGT-701, nucleotide sequence which is differentially expressed in red AGT-702, AGT-704, AGT-705, AGT-706, AGT-707, AGT gastrocnemius tissue of P. obesus under fed or fasted or in 708, AGT-709 and/or AGT-710 activity or AGT-701, AGT exercise trained and control conditions. 702, AGT-704, AGT-705, AGT-706, AGT-707, AGT-708, 0028 More particularly, the present invention is directed AGT-709 and/or AGT-710 gene expression for a time and to an isolated expression product or a derivative, homolog, under conditions sufficient to effect treatment. analog or mimetic thereof wherein the expression product is 0033. In an alternative embodiment, a molecule which encoded by a nucleotide sequence Substantially as set forth modifies accumulation of one or more of AGT-701, AGT in SEQ ID NO:1, SEQ ID NO:2 or SEQ ID NO:3 or SEQ 702, AGT-704, AGT-705, AGT-706, AGT-707, AGT-708, ID NO:4 or SEQID NO:5 or SEQID NO:6 or SEQID NO:7 AGT-709 and/or AGT-710. Such an agent may promote or SEQID NO:8 or SEQID NO:9 or a nucleotide sequence degradation of the target molecule, or may inhibit degrada having at least 30% identity to all or part of SEQID NO:1, tion. SEQID NO:2 or SEQID NO:3 or SEQID NO:4 or SEQID 0034. In accordance with this and other aspects of the NO:5 or SEQ ID NO:6 or SEQ ID NO:7 or SEQ ID NO:8 present invention, treatments contemplated herein include or SEQID NO:9 and/or is capable of hybridizing to SEQ ID but are not limited to healthy state, myopathy, obesity, NO:1, SEQ ID NO:2 or SEQ ID NO:3 or SEQ ID NO:4 or anorexia, weight maintenance, diabetes, disorders associ SEQID NO:5 or SEQID NO:6 or SEQID NO:7 or SEQ ID ated with mitochondrial dysfunction, genetic disorders, can NO:8 or SEQID NO:9 or their complementary forms under cer, heart disease, inflammation, disorders associated with low stringency conditions at 42° C. the immune system, infertility, disease associated with the 0029. The preferred genetic sequence of the present brain and/or metabolic energy levels. Treatment may be by invention are referred to herein as AGT-701, AGT-702, the administration of a pharmaceutical composition or AGT-704, AGT-705, AGT-706, AGT-707, AGT-708, AGT genetic sequences via gene therapy. Treatment is contem 709 and AGT-710. The expression products encoded by plated for human Subjects as well as animals such as animals AGT-701, AGT-702, AGT-704, AGT-705, AGT-706, AGT important to livestock industry. 707, AGT-708, AGT-709 and AGT-710 are referred to herein 0035 A further aspect of the present invention is directed as AGT-701, AGT-702, AGT-704, AGT-705, AGT-706, to a diagnostic agent for use in monitoring or diagnosing AGT-707, AGT-708, AGT-709 and AGT-710, respectively. conditions such as but not limited to healthy state, myopa The expression product may be an RNA (e.g. mRNA) or a thy, obesity, anorexia, weight maintenance, diabetes, disor . Where the expression product is an RNA, the ders associated with mitochondrial dysfunction, genetic present invention extends to RNA-related molecules asso disorders, cancer, heart disease, inflammation, disorders ciated thereto Such as RNAi or intron or exon sequences associated with the immune system, infertility, disease asso therefrom. ciated with the brain and/or metabolic energy levels, said 0030 Even yet another aspect of the present invention diagnostic agent selected from an antibody to AGT-701, relates to a composition comprising AGT-701, AGT-702, AGT-702, AGT-704, AGT-705, AGT-706, AGT-707, AGT AGT-704, AGT-705, AGT-706, AGT-707, AGT-708, AGT 708, AGT-709 and/or AGT-710 or its derivatives, homologs, 709 and/or AGT-710 or its derivatives, homologs, analogs or analogs or mimetics and a genetic sequence comprising or mimetics or agonists or antagonists of AGT-701, AGT-702, capable of annealing to a nucleotide Strand associated with AGT-704, AGT-705, AGT-706, AGT-707, AGT-708, AGT AGT-701, AGT-702, AGT-704, AGT-705, AGT-706, AGT 709 and/or AGT-710 together with one or more pharmaceu 707, AGT-708, AGT-709 or AGT-710 useful inter alia in tically acceptable carriers and/or diluents. PCR, hybridization, RFLP analysis or AFLP analysis.

TABLE 1.

Summary of AGT Genes

GENE SEQ ID NO: HOMOLOG DESCRIPTION

AGT701 1 human, mouse and rat lower expression in Group C, fed NDRG2 animals and higher expression in Group B fasted animals; expression negatively correlated with body fat, US 2007/0021589 A1 Jan. 25, 2007

TABLE 1-continued Summary of AGT Genes GENE SEQ ID NO: HOMOLOG DESCRIPTION body weight and blood glucose in fed animals; increases with exercise training AGT702 2 human, mouse and rat elevated expression after training: PRSS11 negative correlation with body weight and blood glucose; positive correlation with energy expenditure AGT-704 3 human PAI-RBP1 decreased expression in Group C, fed animals; negative correlation with blood glucose in fed animals; increases with exercise training AGT705 4 murine BCO3O414 increased expression in Group C animals and in Group B fasted animals; expression negatively correlated with blood glucose: increases with exercise training AGT-706 5 human FLS20069 elevated expression in Group B murine Ahi-1 fasted and Group C fasted animals; expression negatively correlated with blood glucose in fed animals and positively correlated in insulin in fasted animals; increases with exercise training AGT707 6 human ASNA1 elevated expression in Group A animals; expression negatively correlated with body weight in fed animals; increases with exercise training AGT708 7 human PKIA elevated expression in Group B and Group C fasted animals; expression positively correlated with blood glucose AGT709 8 human KIAAO633, lower expression in Group C, fed Mus musculus similar animals; expression negatively to KIAAO633 correlated with body weight and blood glucose AGT710 9 human, mouse and rat lower expression in Group C, fed SCP2 animals; expression negatively correlated with body weight and blood glucose in fed animals; increases with exercise training

0036) 0037. A summary of sequence identifiers used throughout the subject specification is provided in Table 3.

TABLE 3 TABLE 2 Summary of Sequence Identifiers

Gene Abbreviations SEQUENCE ID NO: DESCRIPTION SOURCE ABBREVIATION DEFINITION 1 Nucleotide sequence of AGT-701 Psammomys obesus 2 Nucleotide sequence of AGT-702 Psammomys obesus NDRG2 N-myc downstream-regulated gene 2 3 Nucleotide sequence of AGT-704 Psammomys obesus 4 Nucleotide sequence of AGT-705 Psammomys obesus PRSS11 protease, serine 11 5 Nucleotide sequence of AGT-706 Psammomys obesus PAI-RBP1 PAI-1 mRNA binding protein 6 Nucleotide sequence of AGT-707 Psammomys obesus ASNA1 human homolog of bacterial arSA arsenite 7 Nucleotide sequence of AGT-708 Psammomys obesus 8 Nucleotide sequence of AGT-709 Psammomys obesus transporter ATP binding 9 Nucleotide sequence of AGT-710 Psammomys obesus PKIA protein kinase inhibitor alpha 10 primer SP6 synthetic SCP2 sterol carrier protein 2 11 primer T7 synthetic 12 peptide synthetic 13 peptide synthetic US 2007/0021589 A1 Jan. 25, 2007

DETAILED DESCRIPTION OF THE 0045 Accordingly, one aspect of the present invention PREFERRED EMBODIMENTS provides a nucleic acid molecule comprising a sequence of nucleotides encoding or complementary to a sequence 0038. The present invention is predicated in part on the encoding an expression product or a derivative, homolog, identification of genes associated inter alia with regulation analog or mimetic thereof wherein said nucleic acid mol of healthy state, myopathy, obesity, anorexia, weight main ecule is differentially expressed in red gastrocnemius muscle tenance, diabetes, disorders associated with mitochondrial tissue of P. obesus under fed and fasted or in exercise trained dysfunction, genetic disorders, cancer, heart disease, inflam and control conditions or a homolog of said nucleic acid mation, disorders associated with the immune system, infer molecule. tility, disease associated with the brain and/or metabolic energy levels. 0046) More particularly, the present invention provides a 0.039 Conveniently, an animal model may be employed molecular marker for a physiological condition selected to study the differences in gene expression in animal tissues from a healthy state, myopathy, obesity, anorexia, weight Such as red gastrocnemius under different conditions. In maintenance, diabetes, disorders associated with mitochon particular, the present invention is exemplified using the P drial dysfunction, genetic disorders, cancer, heart disease, obesus (the Israeli Sand Rat) animal model of dietary inflammation, disorders associated with the immune system, induced obesity and type 2 diabetes. In their natural desert infertility, disease associated with the brain and/or metabolic habitat, an active lifestyle and saltbush diet ensure that they energy levels, wherein said molecular marker comprises a remain lean and normoglycemic (Shafrir and Gutman, J. nucleic acid molecule or an expression product of the Basic Clin. Physiol. Pharm. 4: 83-99, 1993). However, in a nucleic acid molecule which are differentially expressed in laboratory setting on a diet of ad libitum chow (on which at least liver, mesenteric adipose tissue and/or muscle. many other animal species remain healthy), a range of 0047. The term “differentially expressed” is used in its pathophysiological responses are seen (Barnett et al., Dia most general sense and includes elevated levels of an betologia 37: 671-676, 1994a: Barnett et al., Int. J. Obesity expression product such as MRNA or protein or a secondary 18: 789-794, 1994b; Barnett et al., Diabete Nutr Metab. 8: product such as cDNA in one tissue compared to another 42-47, 1995). By the age of 16 weeks, more than half of the tissue or in the same tissue but under different conditions. animals become obese and approximately one third develop Examples of different conditions includes differential type 2 diabetes. Only hyperphagic animals go on to develop expression in tissue from fed and fasted animals or in hyperglycemia, highlighting the importance of excessive exercise trained and control animals. Differential expression energy intake in the pathophysiology of obesity and type 2 is conveniently determined by a range of techniques includ diabetes in P. obesus (Collier et al., Ann. New York Acad. Sci. ing polymerase chain reaction (PCR) such as real-time PCR. 827: 50-63, 1997a; Walder et al., Obesity Res. 5: 193-200, Other techniques include Suppression Subtractive hyridiza 1997a). Other phenotypes found include hyperinsulinemia, tion (SSH) and amplified fragment length polymorphism dyslipidemia and impaired glucose tolerance (Collier et al., (AFLP) analysis. Microarray analysis of cDNA is particu 1997: Collier et al. Exp. Clin. Endocrinol. Diabetes 105: larly preferred. 36-37, 1997b). P. obesus exhibit a range of bodyweight and 0048. A homolog refers to a genetic sequence in another blood glucose and insulin levels which form a continuous animal or organism which has at least about 20% identity to curve that closely resembles the patterns found in human the reference sequence. A preferred homolog is a human populations, including the inverted U-shaped relationship homolog. between blood glucose and insulin levels known as “Star ling's curve of the pancreas” (Barnett et al., 1994a). It is the 0049. It must be noted that, as used in the subject heterogeneity of the phenotypic response of P. obesus which specification, the singular forms “a”, “an and “the include makes it an ideal model to study the etiology and patho plural aspects unless the context clearly dictates otherwise. physiology of obesity and type 2 diabetes. Thus, for example, reference to a 'gene' includes a single 0040. The animals are conveniently classified into three gene, as well as two or more genes; reference to “an active groups designated Groups A, B and C: agent includes a single active agent, as well as two or more active agents; “a condition' includes a single condition or 0041 Group A: animals are lean: two or more conditions and so forth. 0.042 Group B: animals are obese and non-diabetic; and 0050. The expression product may be a protein or MRNA 0.043 Group C: animals are obese and diabetic. or may be an exon or intron spliced, for example, from an RNA construct. The expression product may also be a 0044) In accordance with the present invention, a number hairpin structure which includes or is associated with RNAi. of differentially expressed genetic sequences were identified in red gastrocnemius tissue in P. obesus under different 0051. The selection of gastrocnemius is not intended to feeding regimes (i.e. fed and fasted) or under exercise imply that different expression does not occur in other tissue. trained and control conditions. These genetic sequences 0052 The present invention further extends to homologs have human and other animal homologs and, hence, the identification of these genetic sequences permits identifica in other mammals and in particular humans as well as in tion of genes involved in healthy state, myopathy, obesity, other animals or organisms. anorexia, weight maintenance, diabetes, disorders associ 0053 Another aspect of the present invention provides a ated with mitochondrial dysfunction, genetic disorders, can nucleic acid molecule comprising a nucleotide sequence cer, heart disease, inflammation, disorders associated with encoding or complementary to a sequence encoding an the immune system, infertility, disease associated with the expression product or a derivative, homolog, analog or brain and/or metabolic energy levels. mimetic thereof wherein said nucleotide sequence is as US 2007/0021589 A1 Jan. 25, 2007

substantially set forth in SEQ ID NO:1 (AGT-701) or SEQ cally performed by comparing sequences of the two poly ID NO:2 (AGT-702) or SEQID NO:3 (AGT-704) or SEQID nucleotides over a “comparison window” to identify and NO:4 (AGT-705) or SEQ ID NO:5 (AGT-706) or SEQ ID compare local regions of sequence similarity. A "comparison NO:6 (AGT-707) or SEQ ID NO:7 (AGT-708) or SEQ ID window' refers to a conceptual segment of typically 12 NO:8 (AGT-709) or SEQ ID NO:9 (AGT-710) or a nucle contiguous residues that is compared to a reference otide sequence having at least about 30% identity to all or sequence. The comparison window may comprise additions part of SEQID NO:1 or SEQID NO:2 or SEQID NO:3 or or deletions (i.e. gaps) of about 20% or less as compared to SEQID NO:4 or SEQID NO:5 or SEQID NO:6 or SEQID the reference sequence (which does not comprise additions NO:7 or SEQ ID NO:8 or SEQID NO:9 and/or is capable or deletions) for optimal alignment of the two sequences. of hybridizing to one or more of SEQ ID NO:1 or SEQ ID Optimal alignment of sequences for aligning a comparison NO:2 or SEQID NO:3 or SEQ ID NO:4 or SEQID NO:5 window may be conducted by computerized implementa or SEQID NO:6 or SEQID NO:7 or SEQID NO:8 or SEQ tions of algorithms (GAP, BESTFIT. FASTA, and TFASTA ID NO:9 or their complementary forms under low strin in the Wisconsin Genetics Software Package Release 7.0, gency conditions at 42° C. and wherein said nucleic acid Genetics Computer Group, 575 Science Drive Madison, molecule is differentially expressed in red gastrocnemius Wis., USA) or by inspection and the best alignment (i.e. muscle tissue under fed or fasted or in exercise trained and resulting in the highest percentage homology over the com control conditions. parison window) generated by any of the various methods selected. Reference also may be made to the BLAST family 0054 As indicated above, the preferred homology are of programs as for example disclosed by Altschul et al. derived from human, mouse, or rat, and more preferably (Nucl. Acids Res. 25: 3389, 1997). A detailed discussion of human. sequence analysis can be found in Unit 19.3 of Ausubel et 0055 Reference herein to “similarity” is generally at a al. (“Current Protocols in Molecular Biology' John Wiley & level of comparison of at least 15 consecutive or substan Sons Inc, Chapter 15, 1994-1998). A range of other algo tially consecutive nucleotides or at least 5 consecutive or rithms may be used to compare the nucleotide and amino substantially consecutive amino acid residues. Preferred acid sequences such as but not limited to PILEUP, CLUST percentage similarities have at least about 40%, at least ALW, SEQUENCHER or VectorNTI. about 50%, at least about 60%, at least about 70%, at least 0059. The terms “sequence similarity” and “sequence about 80% and at least about 90% or above. Examples identity” as used herein refers to the extent that sequences include 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, are identical or functionally or structurally similar on a 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, nucleotide-by-nucleotide basis over a window of compari 71, 72, 73, 74, 75, 76, 77,78, 79,80, 81, 82, 83, 84, 85, 86, son. Thus, a "percentage of sequence identity, for example, 87, 88, 89,90,91, 92,93, 94, 95, 96, 97,98, 99 and 100%. is calculated by comparing two optimally aligned sequences 0056. The term “similarity” as used herein includes exact over the window of comparison, determining the number of identity between compared sequences at the nucleotide or positions at which the identical nucleic acid base (e.g. A, T, amino acid level. Where there is non-identity at the nucle C, G, I) occurs in both sequences to yield the number of otide level, “similarity” includes differences between matched positions, dividing the number of matched posi sequences which result in different amino acids that are tions by the total number of positions in the window of nevertheless related to each other at the structural, func comparison (i.e., the window size), and multiplying the tional, biochemical and/or conformational levels. Where result by 100 to yield the percentage of sequence identity. there is non-identity at the amino acid level, “similarity” For the purposes of the present invention, “sequence iden includes amino acids that are nevertheless related to each tity” will be understood to mean the “match percentage” other at the structural, functional, biochemical and/or con calculated by the DNASIS computer program (Version 2.5 formational levels. In a particularly preferred embodiment, for windows; available from Hitachi Software engineering nucleotide and amino acid sequence comparisons are made Co., Ltd., South San Francisco, Calif., USA) using standard at the level of identity rather than similarity. defaults as used in the reference manual accompanying the Software. Similar comments apply in relation to sequence 0057 Reference herein to similarity is generally at a level similarity. of comparison of at least 15 consecutive or Substantially consecutive nucleotides. It is particularly convenient, how 0060 Reference herein to a low stringency includes and ever, to determine similarity by comparing a total or com encompasses from at least about 0 to at least about 15% V/v plete sequence, after optimal alignment. formamide and from at least about 1 M to at least about 2 M salt for hybridization, and at least about 1 M to at least about 0.058 Terms used to describe sequence relationships 2 M salt for washing conditions. Generally, low stringency between two or more polynucleotides include “reference is at from about 25-30° C. to about 42°C., such as 25, 26, sequence', 'comparison window', 'sequence similarity. 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 and "sequence identity”, “percentage of sequence similarity. 42°C. The temperature may be altered and higher tempera "percentage of sequence identity”, “substantially similar tures used to replace formamide and/or to give alternative and “substantial identity”. A “reference sequence' is at least stringency conditions. Alternative Stringency conditions 12 but frequently 15 to 18 and often at least 25 or above, may be applied where necessary, such as medium strin Such as 30 monomer units in length. Because two polynucle gency, which includes and encompasses from at least about otides may each comprise (1) a sequence (i.e. only a portion 16% w/v to at least about 30% V/v formamide, such as 16, 17, of the complete polynucleotide sequence) that is similar 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29 and 30% and between the two polynucleotides, and (2) a sequence that is from at least about 0.5 M to at least about 0.9 M salt, such divergent between the two polynucleotides, sequence com as 0.5,0.6, 0.7, 0.8 or 0.9 M for hybridization, and at least parisons between two (or more) polynucleotides are typi about 0.5 M to at least about 0.9 M salt, such as 0.5,0.6,0.7, US 2007/0021589 A1 Jan. 25, 2007

0.8 or 0.9 M for washing conditions, or high stringency, an expression product wherein said nucleotide sequence is which includes and encompasses from at least about 31% substantially as set forth in SEQ ID NO:1 (AGT-701) or a Viv to at least about 50% V/v formamide, such as 31, 32, 33, derivative, homolog or mimetic thereof or having at least 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49 about 30% identity to all or part of SEQ ID NO:1 or a and 50% and from at least about 0.01 M to at least about 0.15 nucleotide sequence capable of hybridizing to SEQID NO:1 M salt, such as 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, or its complementary form under low stringency conditions. 0.09, 0.10, 0.11, 0.12, 0.13, 0.14 and 0.15 M for hybridiza 0064. Yet another aspect of the present invention pro tion, and at least about 0.01 M to at least about 0.15 M salt, vides a nucleic acid molecule or derivative, homolog or such as 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, analog thereof comprising a nucleotide sequence encoding, 0.10, 0.11, 0.12, 0.13, 0.14 and 0.15 M for washing condi or a nucleotide sequence complementary to a sequence tions. In general, washing is carried out T=69.3+0.41 encoding an expression product wherein said nucleotide (G+C)% (Marmur and Doty, J. Mol. Biol. 5: 109, 1962). However, the T of a duplex DNA decreases by 1° C. with sequence is substantially as set forth in SEQ ID NO:2 every increase of 1% in the number of mismatch base pairs (AGT-702) or a derivative, homolog or mimetic thereof or (Bonner and Laskey, Eur: J. Biochem. 46: 83, 1974. Forma having at least about 30% identity to all or part of SEQ ID mide is optional in these hybridization conditions. Accord NO:2 or a nucleotide sequence capable of hybridizing to ingly, particularly preferred levels of stringency are defined SEQ ID NO:2 or its complementary form under low strin as follows: low stringency is 6xSSC buffer, 0.1% w/v SDS gency conditions. at 25-42°C.; a moderate stringency is 2xSSC buffer, 0.1% 0065. Still yet another aspect of the present invention w/v SDS at a temperature in the range 20°C. to 65°C.; high provides a nucleic acid molecule or derivative, homolog or stringency is 0.1 xSSC buffer, 0.1% w/v SDS at a tempera analog thereof comprising a nucleotide sequence encoding, ture of at least 65° C. or a nucleotide sequence complementary to a sequence encoding an expression product wherein said nucleotide 0061 An expression product includes an RNA molecule sequence is substantially as set forth in SEQ ID NO:3 Such as an mRNA transcript as well as a protein. Some genes (AGT-704) or a derivative, homolog or mimetic thereof or are non-protein encoding genes and produce mRNA or other having at least about 30% identity to all or part of SEQ ID RNA molecules and are involved in regulation by NO:3 or a nucleotide sequence capable of hybridizing to RNA:DNA, RNA:RNA or RNA-protein interaction. The SEQ ID NO:3 or their complementary forms under low RNA (e.g. mRNA) may act directly or via the induction of stringency conditions. other molecules such as RNAi or via products mediated from splicing events (e.g. exons or introns). Other genes 0066 Even yet another aspect of the present invention encode mRNA transcripts which are then translated into provides a nucleic acid molecule or derivative, homolog or . A protein includes a polypeptide. The differentially analog thereof comprising a nucleotide sequence encoding, expressed nucleic acid molecules, therefore, may encode or a nucleotide sequence complementary to a sequence mRNAs only or, in addition, proteins. Both mRNAs and encoding an expression product wherein said nucleotide proteins are forms of “expression products”. sequence is substantially as set forth in SEQ ID NO:4 (AGT-705) or a derivative, homolog or mimetic thereof or 0062) The nucleotide sequence oramino acid sequence of having at least about 30% identity to all or part of SEQ ID the present invention may correspond to exactly the same NO:4 or a nucleotide sequence capable of hybridizing to sequence of the naturally occurring gene (or corresponding SEQ ID NO:4 or its complementary form under low strin cDNA) or protein or other expression product or may carry gency conditions. one or more nucleotide or amino acid substitutions, addi tions and/or deletions. The nucleotide sequences set forth in 0067 Even still another aspect of the present invention SEQ ID NO:1 (AGT-701), SEQ ID NO:2 (AGT-702) and provides a nucleic acid molecule or derivative, homolog or SEQ ID NO:3 (AGT-704) or SEQ ID NO.4 (AGT-705) or analog thereof comprising a nucleotide sequence encoding, SEQ ID NO:5 (AGT-706) or SEQ ID NO:6 (AGT-707) or or a nucleotide sequence complementary to a sequence SEQ ID NO:7 (AGT-708) or SEQ ID NO:8 (AGT-709) or encoding an expression product wherein said nucleotide SEQ ID NO:9 (AGT-710) correspond to novel genes sequence is substantially as set forth in SEQ ID NO:5 referred to in parenthesis. The corresponding expression (AGT-706) or a derivative, homolog or mimetic thereof or products are AGT-701, AGT-702, AGT-704, AGT-705, having at least about 30% identity to all or part of SEQ ID AGT-706, AGT-707, AGT-708, AGT-709 and AGT-710. NO:5 or a nucleotide sequence capable of hybridizing to Reference herein to AGT-701, AGT-702, AGT-704, AGT SEQ ID NO:5 or its complementary form under low strin 705, AGT-706, AGT-707, AGT-708, AGT-709 and AGT-710 gency conditions. includes, where appropriate, reference to the genomic gene 0068 Another aspect of the present invention provides a or cDNA as well as any naturally occurring or induced nucleic acid molecule or derivative, homolog or analog derivatives. Apart from the substitutions, deletions and/or thereof comprising a nucleotide sequence encoding, or a additions to the nucleotide sequence, the present invention nucleotide sequence complementary to a sequence encoding further encompasses mutants, fragments, parts and portions an expression product wherein said nucleotide sequence is of the nucleotide sequence corresponding to AGT-701, substantially as set forth in SEQ ID NO:6 (AGT-707) or a AGT-702, AGT-704, AGT-705, AGT-706, AGT-707, AGT derivative, homolog or mimetic thereof or having at least 708, AGT-709 and AGT-710. about 30% identity to all or part of SEQ ID NO:6 or a 0063 Another aspect of the present invention provides a nucleotide sequence capable of hybridizing to SEQID NO:6 nucleic acid molecule or derivative, homolog or analog or its complementary form under low stringency conditions. thereof comprising a nucleotide sequence encoding, or a 0069. A further aspect of the present invention provides nucleotide sequence complementary to a sequence encoding a nucleic acid molecule or derivative, homolog or analog US 2007/0021589 A1 Jan. 25, 2007 thereof comprising a nucleotide sequence encoding, or a animals (e.g. mice, guinea pigs, hamsters, rabbits), compan nucleotide sequence complementary to a sequence encoding ion animals (e.g. cats, dogs) and captured wild animals (e.g. an expression product wherein said nucleotide sequence is rodents, foxes, deer, kangaroos). Homologs may also be substantially as set forth in SEQ ID NO:7 (AGT-708) or a present in microorganisms and C. elegans. derivative, homolog or mimetic thereof or having at least 0074 The nucleic acids of the present invention and in about 30% identity to all or part of SEQ ID NO:7 or a particular AGT-701, AGT-702, AGT-704, AGT-705, AGT nucleotide sequence capable of hybridizing to SEQID NO:7 706, AGT-707, AGT-708, AGT-709 and AGT-710 and their or its complementary form under low stringency conditions. derivatives and homologs may be in isolated or purified 0070 Yet another aspect of the present invention pro form and/or may be ligated to a vector Such as an expression vides a nucleic acid molecule or derivative, homolog or vector. Expression may be in a eukaryotic cell line (e.g. analog thereof comprising a nucleotide sequence encoding, mammalian, insect or yeast cells) or in prokaryote cells (e.g. or a nucleotide sequence complementary to a sequence E. coli) or in both. By "isolated' is meant a nucleic acid encoding an expression product wherein said nucleotide molecule having undergone at least one purification step and sequence is substantially as set forth in SEQ ID NO:8 this is conveniently defined, for example, by a composition (AGT-709) or a derivative, homolog or mimetic thereof or comprising at least about 10% subject nucleic acid mol having at least about 30% identity to all or part of SEQ ID ecule, preferably at least about 20%, more preferably at least NO:8 or a nucleotide sequence capable of hybridizing to about 30%, still more preferably at least about 40-50%, even SEQ ID NO:8 or its complementary form under low strin still more preferably at least about 60-70%, yet even still gency conditions. more preferably 80-90% or greater of subject nucleic acid molecule relative to other components as determined by 0071. Still another aspect of the present invention pro molecular weight, encoding activity, nucleotide sequence, vides a nucleic acid molecule or derivative, homolog or base composition or other convenient means. The nucleic analog thereof comprising a nucleotide sequence encoding, acid molecule of the present invention may also be consid or a nucleotide sequence complementary to a sequence ered, in a preferred embodiment, to be biologically pure. The encoding an expression product wherein said nucleotide nucleic acid molecule may be ligated to an expression vector sequence is substantially as set forth in SEQ ID NO:9 capable of expression in a prokaryotic cell (e.g. E. coli) or (AGT-710) or a derivative, homolog or mimetic thereof or a eukaryotic cell (e.g. yeast cells, fungal cells, insect cells, having at least about 30% identity to all or part of SEQ ID mammalian cells or plant cells). The nucleic acid molecule NO:9 or a nucleotide sequence capable of hybridizing to may be ligated or fused or otherwise associated with a SEQ ID NO:9 or its complementary form under low strin nucleic acid molecule encoding another entity Such as, for gency conditions. example, a signal peptide. It may also comprise additional 0072 The expression pattern of AGT-701, AGT-702, nucleotide sequence information fused, linked or otherwise AGT-704, AGT-705, AGT-706, AGT-707, AGT-708, AGT associated with it either at the 3' or 5' terminal portions or at 709 and AGT-710 has been determined, interalia, to indicate both the 3' and 5' terminal portions. The nucleic acid an involvement in the regulation of one or more of healthy molecule may also be part of a vector, such as an expression state, myopathy, obesity, anorexia, weight maintenance, Vector. diabetes, disorders associated with mitochondrial dysfunc 0075) The derivatives of the nucleic acid molecule of the tion, genetic disorders, cancer, heart disease, inflammation, present invention include oligonucleotides, PCR primers, disorders associated with the immune system, infertility, antisense molecules, molecules Suitable for use in co-Sup disease associated with the brain and/or metabolic energy pression and fusion nucleic acid molecules. Ribozymes and levels. In addition to the differential expression of AGT-701, DNAZymes are also contemplated by the present invention AGT-702, AGT-704, AGT-705, AGT-706, AGT-707, AGT directed to AGT-701, AGT-702, AGT-704, AGT-705, AGT 708, AGT-709 and AGT-710 in red gastrocnemius muscle of 706, AGT-707, AGT-708, AGT-709 and AGT-710 or their fed versus fasted or exercise trained versus control animals, mRNAs. Derivatives and homologs of AGT-701, AGT-702, these genes may also be expressed in other tissues including AGT-704, AGT-705, AGT-706, AGT-707, AGT-708, AGT but in no way limited to brain, muscle, adipose tissue, 709 and AGT-710 are conveniently encompassed by those pancreas and gastrointestinal trait. The nucleic acid mol nucleotide sequences capable of hybridizing to one or more ecule corresponding to each of AGT-701, AGT-702, AGT of SEQID NO:1, SEQ ID NO:2 or SEQ ID NO:3 or SEQ 704, AGT-705, AGT-706, AGT-707, AGT-708, AGT-709 or ID NO:4 or SEQID NO:5 or SEQID NO:6 or SEQID NO:7 AGT-710 is preferably a DNA such as a cDNA sequence or or SEQ ID NO:8 or SEQ ID NO:9 or their complementary a genomic DNA. A genomic sequence may also comprise forms under low stringency conditions. exons and introns. A genomic sequence may also include a 0076) Derivatives include fragments, parts, portions, promoter region or other regulatory regions. mutants, variants and mimetics from natural, synthetic or 0073. A homolog is considered to be a gene from another recombinant sources including fusion nucleic acid mol animal species which has the same or greater than 30% ecules. Derivatives may be derived from insertion, deletion similarity to one of AGT-701, AGT-702, AGT-704, AGT or substitution of nucleotides. 705, AGT-706, AGT-707, AGT-708, AGT-709 and AGT-710 0077. Another aspect of the present invention provides an and/or which has a similar function. The above-mentioned isolated expression product or a derivative, homolog, analog genes are exemplified herein from P. obesus red gastrocne or mimetic thereof which is produced in larger or lesser mius muscle. The present invention extends, however, to the amounts in red gastrocnemius muscle in obese animals homologous gene, as determined by nucleotide sequence compared to lean animals or in fed (including re-fed) and/or function, from humans, primates, livestock animals compared to fasted animals or in animals under exercise (e.g. cows, sheep, pigs, horses, donkeys), laboratory test trained compared to control conditions. US 2007/0021589 A1 Jan. 25, 2007

0078. An expression product, as indicated above, may be and AGT-710 include chemical analogs. Analogs of AGT RNA or protein. Insofar as the product is a protein, deriva 701, AGT-702, AGT-704, AGT-705, AGT-706, AGT-707, tives include amino acid insertional derivatives such as AGT-708, AGT-709 and AGT-710 contemplated herein amino and/or carboxylic terminal fusions as well as intra include, but are not limited to, modifications to side chains, sequence insertions of single or multiple amino acids. Inser incorporation of unnatural amino acids and/or their deriva tional amino acid sequence variants are those in which one tives during peptide, polypeptide or protein synthesis and or more amino acid residues are introduced into a predeter the use of crosslinkers and other methods which impose mined site in a protein although random insertion is also confirmational constraints on the proteinaceous molecule or possible with Suitable screening of the resulting product. their analogs. Deletional variants are characterized by the removal of one or more amino acids from the sequence. Substitutional 0084 Examples of side chain modifications contem amino acid variants are those in which at least one residue plated by the present invention include modifications of in the sequence has been removed and a different residue amino groups such as by reductive alkylation by reaction inserted in its place. An example of Substitutional amino acid with an aldehyde followed by reduction with NaBH; amidi variants are conservative amino acid Substitutions. Conser nation with methylacetimidate; acylation with acetic anhy Vative amino acid substitutions typically include Substitu tions within the following groups: and alanine; dride; carbamoylation of amino groups with cyanate; trini , and ; and glutamic trobenzylation of amino groups with 2,4,6-trinitrobenzene acid; asparagine and ; serine and threonine; sulfonic acid (TNBS); acylation of amino groups with and ; and and . Additions to Succinic anhydride and tetrahydrophthalic anhydride; and amino acid sequences include fusions with other peptides, pyridoxylation of lysine with pyridoxal-5-phosphate fol polypeptides or proteins. lowed by reduction with NaBH4. 0079 Chemical and functional equivalents of protein 0085. The guanidine group of arginine residues may be forms of the expression products AGT-701, AGT-702, AGT modified by the formation of heterocyclic condensation 704, AGT-705, AGT-706, AGT-707, AGT-708, AGT-709 or products with reagents such as 2,3-butanedione, phenylgly AGT-710 should be understood as molecules exhibiting any oxal and glyoxal. one or more of the functional activities of these molecules and may be derived from any source Such as being chemi 0086) The carboxyl group may be modified by carbodi cally synthesized or identified via screening processes such imide activation via O-acylisourea formation followed by as natural product screening or screening of chemical librar Subsequent derivitization, for example, to a corresponding 1CS amide. 0080. The derivatives include fragments having particu 0087 Sulphydryl groups may be modified by methods lar epitopes or parts of the entire protein fused to peptides, Such as carboxymethylation with iodoacetic acid or iodoac polypeptides or other proteinaceous or non-proteinaceous etamide; performic acid oxidation to cysteic acid; formation molecules. of a mixed disulphides with other thiol compounds; reaction 0081) Derivatives include fragments, parts, portions, with maleimide, maleic anhydride or other substituted male mutants, polymorphisms, variants and mimetics from natu imide; formation of mercurial derivatives using 4-chlo ral, synthetic or recombinant sources including fusion romercuribenzoate, 4-chloromercuriphenylsulphonic acid, nucleic acid molecules. Derivatives may be derived from phenylmercury chloride, 2-chloromercuri-4-nitrophenol and insertion, deletion or substitution of nucleotides. other mercurials; carbamoylation with cyanate at alkaline 0082) Reference herein to AGT-701, AGT-702, AGT-704, pH. AGT-705, AGT-706, AGT-707, AGT-708, AGT-709 or 0088 residues may be modified by, for AGT-710 includes reference to isolated or purified naturally example, oxidation with N-bromosuccinimide or alkylation occurring AGT-701-AGT-702, AGT-704, AGT-705, AGT of the indole ring with 2-hydroxy-5-nitrobenzyl bromide or 706, AGT-707, AGT-708, AGT-709 or AGT-710 as well as any derivatives, homologs, analogs and mirnmetics thereof: Sulphenyl halides. Tyrosine residues on the other hand, may Derivatives include parts, fragments and portions AGT-701, be altered by nitration with tetranitromethane to form a AGT-702, AGT-704, AGT-705, AGT-706, AGT-707, AGT 3-nitrotyrosine derivative. 708, AGT-709 or AGT-710 as well as single and multiple 0089 Modification of the imidazole ring of a amino acid substitutions, deletions and/or additions to AGT residue may be accomplished by alkylation with iodoacetic 701, AGT-702, AGT-704, AGT-705, AGT-706, AGT-707, acid derivatives or N-carbethoxylation with diethylpyrocar AGT-708, AGT-709 and AGT-710 when the expression products are proteins. A derivative of AGT-701, AGT-702, bonate. AGT-704, AGT-705, AGT-706, AGT-707, AGT-708, AGT 0090. Examples of incorporating unnatural amino acids 709 or AGT-710 is conveniently encompassed by molecules and derivatives during peptide synthesis include, but are not encoded by a nucleotide sequence capable of hybridizing to limited to, use of norleucine, 4-aminobutyric acid, 4-amino SEQID NO:1 or SEQID NO:2 or SEQID NO:3 or SEQID 3-hydroxy-5-phenylpentanoic acid, 6-aminohexanoic acid, NO:4 or SEQ ID NO:5 or SEQ ID NO:6 or SEQ ID NO:7 t-butylglycine, norvaline, phenylglycine, ornithine, Sar or SEQ ID NO:8 or SEQ ID NO:9 under low stringency conditions. cosine, 4-amino-3-hydroxy-6-methylheptanoic acid, 2-thie nyl alanine and/or D-isomers of amino acids. A list of 0083) Other derivatives of AGT-701, AGT-702, AGT unnatural amino acid, contemplated herein is shown in Table 704, AGT-705, AGT-706, AGT-707, AGT-708, AGT-709 4.

US 2007/0021589 A1 Jan. 25, 2007 11

TABLE 4-continued

Codes for non-conventional amino acids

Non-conventional Non-conventional amino acid Code amino acid Code L-C.-methylarginine Marg L-C.-methylasparagine Masin L-C.-methylaspartate Masp L-C.-methyl-t-butylglycine Mtbug L-C.-methylcysteine Mcys L-methylethylglycine Metg L-C.-methylglutamine Mglin L-C.-methylglutamate Mglu L-C-methylhistidine Mhis L-C.-methylhomophenylalanine Mhphe L-C.-methylisoleucine Mile N-(2-methylthioethyl)glycine Nmet L-C.-methyleucine Meu L-C.-methyllysine Mlys L-C.-methylmethionine Mmet L-C.-methylmorleucine Minle L-C.-methylnorvaline Mnva L-C.-methylornithine Morn L-C-methylphenylalanine Mphe L-C.-methylproline Mpro L-C.-methylserine Miser L-C.-methylthreonine Mthir L-C.-methyltryptophan Mtrp L-C.-methyltyrosine Mtyr L-C-methylvaline Mval L-N-methylhomophenylalanine Nmhphe N-(N-(2,2-diphenylethyl) Nnbhm N-(N-(3,3-diphenylpropyl) Nnbhe carbamylmethyl)glycine carbamylmethyl)glycine -carboxy-1-(2,2-diphenyl- Nmbc ethylamino)cyclopropane

0.091 Crosslinkers can be used, for example, to stabilize 0096. In another particularly preferred embodiment, the 3D conformations, using homo-bifunctional crosslinkers expression product is encoded by a sequence of nucleotides Such as the bifunctional imido esters having (CH), spacer comprising SEQ ID NO:2 or a derivative, homolog or groups with n=1 to n=6, glutaraldehyde, N-hydroxysuccin analog thereof including a nucleotide sequence having at imide esters and hetero-bifunctional reagents which usually least about 30% identity to SEQ ID NO:2 or a nucleotide contain an amino-reactive moiety Such as N-hydroxysuccin sequence capable of hybridizing to SEQ ID NO:2 or its imide and another group specific-reactive moiety such as complementary form under low stringency conditions. maleimido or dithio moiety (SH) or carbodiimide (COOH). 0097. In still another particularly preferred embodiment, In addition, peptides can be conformationally constrained the expression product is encoded by a sequence of nucle by, for example, incorporation of C, and N-methylamino otides comprising SEQID NO:3 or a derivative homolog or acids, introduction of double bonds between C. and C. analog thereof including a nucleotide sequence having at atoms of amino acids and the formation of cyclic peptides or least about 30% identity to SEQ ID NO:3 or a nucleotide analogs by introducing covalent bonds such as forming an sequence capable of hybridizing to SEQ ID NO:3 or their amide bond between the N and C termini, between two side chains or between a side chain and the N or C terminus. complementary form under low stringency conditions. 0098. In yet another particularly preferred embodiment, 0092 All such modifications may also be useful in sta the expression product is encoded by a sequence of nucle bilizing the AGT-701, AGT-702, AGT-704, AGT-705, AGT otides comprising SEQID NO:4 or a derivative homolog or 706, AGT-707, AGT-708, AGT-709 and AGT-710 molecule analog thereof including a nucleotide sequence having at for use in in vivo administration protocols or for diagnostic least about 30% identity to SEQ ID NO:4 or a nucleotide purposes. sequence capable of hybridizing to SEQ ID NO:4 or their 0093. As stated above, the expression product may be a complementary form under low stringency conditions. RNA or protein. 0099. In another particularly preferred embodiment, the 0094. The term “protein’ should be understood to encom expression product is encoded by a sequence of nucleotides pass peptides, polypeptides and proteins. The protein may be comprising SEQID NO:5 or a derivative homolog or analog glycosylated or unglycosylated and/or may contain a range thereof including a nucleotide sequence having at least about of other molecules fused, linked, bound or otherwise asso 30% identity to SEQ ID NO:5 or a nucleotide sequence ciated to the protein such as amino acids, lipids, carbohy capable of hybridizing to SEQ ID NO:5 or its complemen drates or other peptides, polypeptides or proteins. Reference tary form under low stringency conditions. hereinafter to a “protein’ includes a protein comprising a 0100. In still another particularly preferred embodiment, sequence of amino acids as well as a protein associated with the expression product is encoded by a sequence of nucle other molecules Such as amino acids, lipids, carbohydrates otides comprising SEQID NO:6 or a derivative homolog or or other peptides, polypeptides or proteins. analog thereof including a nucleotide sequence having at least about 30% identity to SEQ ID NO:6 or a nucleotide 0.095. In a particularly preferred embodiment, the expres sequence capable of hybridizing to SEQ ID NO:6 or its sion product is encoded by a sequence of nucleotides comprising SEQ ID NO:1 or a derivative, homolog or complementary form under low stringency conditions. analog thereof including a nucleotide sequence having at 0101. In a further particularly preferred embodiment, the least about 30% identity to SEQ ID NO:1 or a nucleotide expression product is encoded by a sequence of nucleotides sequence capable of hybridizing to SEQ ID NO:1 or its comprising SEQID NO:7 or a derivative homolog or analog complementary form under low stringency conditions. thereof including a nucleotide sequence having at least about US 2007/0021589 A1 Jan. 25, 2007

30% identity to SEQ ID NO:7 or a nucleotide sequence amino acid sequence having at least about 30% simi capable of hybridizing to SEQ ID NO:7 or its complemen larity to these sequences or a derivative, homolog, tary form under low stringency conditions. analog, chemical equivalent or mimetic of said protein; 0102) In still yet another particularly preferred embodi 0112 (viii) a protein comprising an amino acid ment, the expression product is encoded by a sequence of sequence substantially as set forth in SEQID NO:4 or nucleotides comprising SEQ ID NO:8 or a derivative a derivative, homolog or analog thereof or a sequence homolog or analog thereof including a nucleotide sequence encoding an amino acid sequence having at least about having at least about 30% identity to SEQ ID NO:8 or a 30% similarity to these sequences or a derivative, nucleotide sequence capable of hybridizing to SEQID NO:8 homolog, analog, chemical equivalent or mimetic of or its complementary form under low stringency conditions. said protein; 0103) In yet another particularly preferred embodiment, 0113 (ix) a protein encoded by a nucleotide sequence the expression product is encoded by a sequence of nucle substantially comprising SEQID NO:5 or a derivative, otides comprising SEQID NO:9 or a derivative homolog or homolog or analog thereof or a sequence encoding an analog thereof including a nucleotide sequence having at amino acid sequence having at least about 30% simi least about 30% identity to SEQ ID NO:9 or a nucleotide larity to this sequence or a derivative, homolog, analog, sequence capable of hybridizing to SEQ ID NO:9 or its chemical equivalent or mimetic of said protein; complementary form under low stringency conditions. 0114 (x) a protein encoded by a nucleotide sequence 0104 Higher similarities are also contemplated by the substantially comprising SEQID NO:6 or a derivative, present invention such as greater than 40% or 50% or 60% homolog or analog thereof or a sequence encoding an or 70% or 80% or 90% or 95% or 96% or 97% or 98% or amino acid sequence having at least about 30% simi 99% or above. Further examples include 40, 41, 42, 43, 44. larity to this sequence or a derivative, homolog, analog, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, chemical equivalent or mimetic of said protein; 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72,73, 74, 75, 76, 0115 (xi) a protein encoded by a nucleotide sequence 77,78, 79,80, 81, 82, 83, 84,85, 86, 87, 88, 89,90,91, 92, substantially comprising SEQID NO:7 or a derivative, 93, 94, 95, 96, 97,98, 99 and 100%. homolog or analog thereof or a sequence encoding an 0105. Another aspect of the present invention is directed amino acid sequence having at least about 30% simi to an isolated expression product selected from the list larity to this sequence or a derivative, homolog, analog, consisting of: chemical equivalent or mimetic of said protein; 0106 (i) an MRNA or protein encoded by a novel 0116 (xii) a protein encoded by a nucleotide sequence nucleic acid molecule which molecule is differentially substantially comprising SEQID NO:8 or a derivative, expressed in red gastrocnemius muscle from P. obesus homolog or analog thereof or a sequence encoding an animals under fed or fasting conditions or in exercise amino acid sequence having at least about 30% simi trained and control animals or a derivative, homolog, larity to this sequence or a derivative, homolog, analog, analog, chemical equivalent or mimetic thereof; chemical equivalent or mimetic of said protein; 0107 (ii) an MRNA or protein encoded by a novel 0.117 (xiii) a protein encoded by a nucleotide sequence nucleic acid molecule which molecule is differentially substantially comprising SEQID NO:9 or a derivative, expressed in red gastrocnemius muscle from P. obesus homolog or analog thereof or a sequence encoding an animals under fed or fasting conditions or in exercise amino acid sequence having at least about 30% simi trained and control animals or a derivative, homolog, larity to this sequence or a derivative, homolog, analog, analog, chemical equivalent or mimetic thereof; chemical equivalent or mimetic of said protein; 0118 (xiv) a protein encoded by a nucleic acid mol 0108 (iii) AGT-701, AGT-702, AGT-704, AGT-705, ecule capable of hybridizing to a nucleotide sequence AGT-706, AGT-707, AGT-708, AGT-709 or AGT-710 comprising SEQ ID NO:1 or its complementary form or a derivative, homolog, analog, chemical equivalent or or a derivative, homolog or analog thereof under low mimetic thereof; stringency conditions; 0.109 (iv) a protein encoded by a nucleotide sequence 0119 (XV) a protein encoded by a nucleic acid mol comprising SEQ ID NO:1 or a derivative, homolog or ecule capable of hybridizing to a nucleotide sequence analog thereof or a sequence encoding an amino acid comprising SEQ ID NO:2 or its complementary form sequence having at least about 30% similarity to this or a derivative, homolog or analog thereof under low sequence or a derivative, homolog, analog, chemical stringency conditions; equivalent or mimetic of said protein; 0120 (xvi) a protein encoded by a nucleic acid mol 0110 (vi) a protein encoded by a nucleotide sequence ecule capable of hybridizing to a nucleotide sequence substantially comprising SEQID NO:2 or a derivative, comprising SEQ ID NO:3 or their complementary homolog or analog thereof or a sequence encoding an forms or a derivative, homolog or analog thereof under amino acid sequence having at least about 30% simi low stringency conditions; larity to this sequence or a derivative, homolog, analog, 0121 (xvii) protein encoded by a nucleic acid mol chemical equivalent or mimetic of said protein; ecule capable of hybridizing to a nucleotide sequence 0.111 (vii) a protein encoded by a nucleotide sequence comprising SEQ ID NO:4 or their complementary substantially comprising SEQID NO:3 or a derivative, forms or a derivative, homolog or analog thereof under homolog or analog thereof or a sequence encoding an low stringency conditions; US 2007/0021589 A1 Jan. 25, 2007 13

0.122 (xviii) a protein encoded by a nucleic acid mol and AGT-710 permits the generation of a range of thera ecule capable of hybridizing to a nucleotide sequence peutic molecules capable of modulating expression of AGT comprising SEQ ID NO:5 or its complementary form 701, AGT-702, AGT-704, AGT-705, AGT-706, AGT-707, or a derivative, homolog or analog thereof under low AGT-708, AGT-709 and AGT-710 or modulating the activity stringency conditions; of AGT-701, AGT-702, AGT-704, AGT-705, AGT-706, 0123 (xix) a protein encoded by a nucleic acid mol AGT-707, AGT-708, AGT-709 and AGT-710 and/or which ecule capable of hybridizing to a nucleotide sequence modulate levels of the expression products (i.e. agents which comprising SEQ ID NO:6 or its complementary form affect the accumulation of the products). Modulators con or a derivative, homolog or analog thereof under low templated by the present invention include agonists and stringency conditions; antagonists of AGT-701, AGT-702, AGT-704, AGT-705, AGT-706, AGT-707, AGT-708, AGT-709 and AGT-710 0.124 (XX) a protein encoded by a nucleic acid mol expression. Antagonists of AGT-701, AGT-702, AGT-704, ecule capable of hybridizing to a nucleotide sequence AGT-705, AGT-706, AGT-707, AGT-708, AGT-709 and comprising SEQ ID NO:7 or its complementary form AGT-710 expression include antisense molecules, or a derivative, homolog or analog thereof under low ribozymes and co-suppression molecules (including any stringency conditions; molecules which induce RNAi). Agonists include molecules 0.125 (xxi) a protein encoded by a nucleic acid mol which increase promoter activity or which interfere with ecule capable of hybridizing to a nucleotide sequence negative regulatory mechanisms. Antagonists of AGT-701, comprising SEQ ID NO:8 or its complementary form AGT-702, AGT-704, AGT-705, AGT-706, AGT-707, AGT or a derivative, homolog or analog thereof under low 708, AGT-709 and AGT-710 include antibodies and inhibi stringency conditions; and tor peptide fragments. All Such molecules may first need to 0.126 (xxii) a protein encoded by a nucleic acid mol be modified to enable such molecules to penetrate cell ecule capable of hybridizing to a nucleotide sequence membranes. Alternatively, viral agents may be employed to comprising SEQ ID NO:9 or its complementary form introduce genetic elements to modulate expression of AGT or a derivative, homolog or analog thereof under low 701, AGT-702, AGT-704, AGT-705, AGT-706, AGT-707, stringency conditions. AGT-708, AGT-709 and AGT-710. In so far as AGT-701, 0127. The protein of the present invention is preferably in AGT-702, AGT-704, AGT-705, AGT-706, AGT-707, AGT isolated form. By "isolated” is meant a protein having 708, AGT-709 and AGT-710 act in association with other undergone at least one purification step and this is conve genes such as the ob gene which encodes leptin, the thera niently defined, for example, by a composition comprising at peutic molecules may target AGT-701, AGT-702, AGT-704, least about 10% subject protein, preferably at least about AGT-705, AGT-706, AGT-707, AGT-708, AGT-709 and 20%, more preferably at least about 30%, still more prefer AGT-710 and ob genes or their translation products. ably at least about 40-50%, even still more preferably at 0.130. The present invention contemplates, therefore, a least about 60-70%, yet even still more preferably 80-90% method for modulating expression of AGT-701, AGT-702, or greater, such as 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, AGT-704, AGT-705, AGT-706, AGT-707, AGT-708, AGT 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 709 and AGT-710 in a mammal, said method comprising 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, contacting the AGT-701, AGT-702, AGT-704, AGT-705, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, AGT-706, AGT-707, AGT-708, AGT-709 and AGT-710 69, 70, 71, 72,73, 74, 75, 76, 77, 78, 79,80, 81, 82, 83, 84, gene with an effective amount of a modulator of AGT-701, 85, 86, 87, 88, 89,90,91, 92,93, 94, 95, 96, 97,98, 99 and AGT-702, AGT-704, AGT-705, AGT-706, AGT-707, AGT 100% of subject protein relative to other components as 708, AGT-709 and AGT-710 expression for a time and under determined by molecular weight, amino acid sequence or conditions sufficient to up-regulate or down-regulate or other convenient means. The protein of the present invention otherwise modulate expression of AGT-701, AGT-702, may also be considered, in a preferred embodiment, to be AGT-704, AGT-705, AGT-706, AGT-707, AGT-708, AGT biologically pure. 709 and AGT-710. 0128. Without limiting the theory or mode of action of 0131 For example, a nucleic acid molecule encoding the present invention, the expression of AGT-701, AGT-702, AGT-701, AGT-702, AGT-704, AGT-705, AGT-706, AGT AGT-704, AGT-705, AGT-706, AGT-707, AGT-708, AGT 707, AGT-708, AGT-709 and AGT-710 or a derivative or 709 and AGT-710 is thought to relate to regulation of body homolog thereof may be introduced into a cell to enhance weight and glucose homeostasis. Modulation of expression the ability of that cell to produce AGT-701, AGT-702, of these genes is thought interalia to regulate energy balance AGT-704, AGT-705, AGT-706, AGT-707, AGT-708, AGT via effects on energy intake and also effects on carbohydrate/ 709 and AGT-710, conversely, AGT-701, AGT-702, AGT fat metabolism. The energy intake effects are likely to be 704, AGT-705, AGT-706, AGT-707, AGT-708, AGT-709 mediated via the central nervous system but peripheral and AGT-710 sense and/or antisense sequences such as effects on the metabolism of both carbohydrate and fat are oligonucleotides may be introduced to decrease expression possible. The expression of these genes may also be regu of the genes at the level of transcription, post-transcription lated by fasting and feeding. Accordingly, regulating the or translation. Sense sequences preferably encode hair pin expression and/or activity of these genes or their expression RNA molecules or double-stranded RNA molecules. products provides a mechanism for regulating both body weight and energy metabolism, including carbohydrate and 0132) Another aspect of the present invention contem fat metabolism. plates a method of modulating activity of AGT-701, AGT 702, AGT-704, AGT-705, AGT-706, AGT-707, AGT-708, 0129. The identification of AGT-701, AGT-702, AGT AGT-709 and AGT-710 in a mammal, said method com 704, AGT-705, AGT-706, AGT-707, AGT-708, AGT-709 prising administering to said mammal a modulating effective US 2007/0021589 A1 Jan. 25, 2007

amount of a molecule for a time and under conditions to increase or decrease AGT-701, AGT-702, AGT-704, AGT sufficient to increase or decrease AGT-701, AGT-702, AGT 705, AGT-706, AGT-707, AGT-708, AGT-709 and/or AGT 704, AGT-705, AGT-706, AGT-707, AGT-708, AGT-709 710 activity or function. and AGT-710 activity. The molecule may be a proteinaceous 0.138 Modulation of activity by the administration of an molecule or a chemical entity and may also be a derivative agent to a mammal can be achieved by one of several of AGT-701, AGT-702, AGT-704, AGT-705, AGT-706, techniques, including, but in no way limited to, introducing AGT-707, AGT-708, AGT-709 and AGT-710 or its ligand. into a mammal a proteinaceous or non-proteinaceous mol 0.133 Still another aspect of the present invention con ecule which: templates a method of modulating the accumulation of AGT-701, AGT-702, AGT-704, AGT-705, AGT-706, AGT 0139 (i) modulates expression of AGT-701, AGT-702, 707, AGT-708, AGT-709 and AGT-710 in a mammal, said AGT-704, AGT-705, AGT-706, AGT-707, AGT-708, method comprising administering to said mammal a modu AGT-709 and/or AGT-710; lating effective amount of a molecule for a time and under 0140 (ii) functions as an antagonist of AGT-701, AGT conditions sufficient to increase or decrease AGT-701, AGT 702, AGT-704, AGT-705, AGT-706, AGT-707, AGT 702, AGT-704, AGT-705, AGT-706, AGT-707, AGT-708, 708, AGT-709 and/or AGT-710; and/or AGT-709 and AGT-710 levels. 0.141 (iii) functions as an agonist of AGT-701, AGT 0134) Modulating levels of AGT-701, AGT-702, AGT 702, AGT-704, AGT-705, AGT-706, AGT-707, AGT 704, AGT-705, AGT-706, AGT-707, AGT-708, AGT-709 708, AGT-709 and/or AGT-710. and AGT-710 expression or AGT-701, AGT-702, AGT-704, AGT-705, AGT-706, AGT-707, AGT-708, AGT-709 and/or 0142. The molecules which may be administered to a AGT-710 activity or function is important in the treatment of mammal in accordance with the present invention may also a range of conditions such as healthy State, myopathy, be linked to a targeting means such as a monoclonal anti obesity, anorexia, weight maintenance, diabetes, disorders body, which provides specific delivery of these molecules to associated with mitochondrial dysfunction, genetic disor the target cells. ders, cancer, heart disease, inflammation, disorders associ ated with the immune system, infertility, disease associated 0.143 A further aspect of the present invention relates to with the brain and/or metabolic energy levels. It may also be the use of the invention in relation to mammalian disease useful in the agricultural industry to assist in the generation conditions. For example, the present invention is particularly of leaner animals, or where required, more obese animals. useful in a therapeutic or prophylactic treatment of healthy Accordingly, mammals contemplated by the present inven state, myopathy, obesity, anorexia, weight maintenance, tion include but are not limited to humans, primates, live diabetes, disorders associated with mitochondrial dysfunc stock animals (e.g. pigs, sheep, cows, horses, donkeys), tion, genetic disorders, cancer, heart disease, inflammation, laboratory test animals (e.g. mice, rats, guinea pigs, ham disorders associated with the immune system, infertility, sters, rabbits), companion animals (e.g. dogs, cats) and disease associated with the brain and/or metabolic energy captured wild animals (e.g. foxes, kangaroos, deer). A par levels. ticularly preferred host is a human, primate or livestock 0144. Accordingly, another aspect of the present inven animal. tion relates to a method of treating a mammal Suffering from 0135). Accordingly, the present invention contemplates a condition characterized by one or more symptoms of therapeutic and prophylactic use of AGT-701, AGT-702, healthy state, myopathy, obesity, anorexia, weight mainte AGT-704, AGT-705, AGT-706, AGT-707, AGT-708, AGT nance, diabetes, disorders associated with mitochondrial 709 and/or AGT-710 expression products or AGT-701, AGT dysfunction, genetic disorders, cancer, heart disease, inflam 702, AGT-704, AGT-705, AGT-706, AGT-707, AGT-708, mation, disorders associated with the immune system, infer AGT-709 and AGT-710 genetic mutants and/or agonists or tility, disease associated with the brain and/or metabolic antagonists agents thereof. energy levels, said method comprising administering to said mammal an effective amount of an agent for a time and 0136. The present invention contemplates, therefore, a under conditions Sufficient to modulate the expression of method of modulating expression of AGT-701, AGT-702, AGT-701, AGT-762, AGT-704, AGT-705, AGT-706, AGT AGT-704, AGT-705, AGT-706, AGT-707, AGT-708, AGT 707, AGT-708, AGT-709 and/or AGT-710 or sufficient to 709 and/or AGT-710 in a mammal, said method comprising modulate the activity of AGT-701, AGT-702, AGT-704, contacting the AGT-701, AGT-702, AGT-704, AGT-705, AGT-705, AGT-706, AGT-707, AGT-708, AGT-709 and/or AGT-706, AGT-707, AGT-708, AGT-709 and/or AGT-710 AGT710. genes with an effective amount of an agent for a time and under conditions Sufficient to up-regulate, down-regulate or 0145. In another aspect, the present invention relates to a otherwise module expression of AGT-701, AGT-702, AGT method of treating a mammal Suffering from a disease 704, AGT-705, AGT-706, AGT-707, AGT-708, AGT-709 condition characterized by one or more symptoms of healthy and AGT-710. state, myopathy, obesity, anorexia, weight maintenance, diabetes, disorders associated with mitochondrial dysfunc 0137 Another aspect of the present invention contem tion, genetic disorders, cancer, heart disease, inflammation, plates a method of modulating activity of AGT-701, AGT disorders associated with the immune system, infertility, 702, AGT-704, AGT-705, AGT-706, AGT-707, AGT-708, disease associated with the brain and/or metabolic energy AGT-709 and/or AGT-710 in a subject, said method com levels, said method comprising administering to said mam prising administering to said Subject a modulating effective mal an effective amount of AGT-701, AGT-702, AGT-704, amount of an agent for a time and under conditions Sufficient AGT-705, AGT-706, AGT-707, AGT-708, AGT-709 and/or US 2007/0021589 A1 Jan. 25, 2007

AGT-710 or AGT-701, AGT-702 AGT-704, AGT-705, AGT 0152 Symptoms which affect the kidneys include proxi 706, AGT-707, AGT-708, AGT-709 and/or AGT-710. mal renal tubular wasting resulting in loss of protein, mag nesium, phosphorous, calcium and other electrolytes. 0146). As used herein “myopathy' refers to any abnormal conditions or disease of the muscle tissues, which include 0.153 Symptoms which affect the heart include cardiac the muscles over our bones (skeletal muscle) and the heart conduction defects heart blocks) and cardio myopathy. (cardiac muscle). 0154 Symptoms which affect the liver include hypogly cemia (low blood sugar) and liver failure. 0147 Obesity, inter alia myopathy, anorexia, diabetes and disorders associated with imbalances in metabolic 0.155 Symptoms which affect the eyes include visual loss energy levels, including any condition associated with vary and blindness. ing levels of selenoproteins are disease and disorders asso 0156 Symptoms which affect the ears include hearing ciated with mitochondrial dysfunction, and genetic disor loss and deafness. ders. Mitochondria are part of the cell (organelle) that is responsible for energy production. The organelle consists of 0157) Symptoms which affect the pancreas include dia two sets of membranes, a smooth continuous outer coat and betes and exocrine pancreatic failure (inability to make an inner membrane arranged in tubules or in folds that form digestive enzymes). plate-like double membranes (cristae). Mitochondria are the 0158. There may also be systemic problems associated principal energy source of the cell, containing the cyto with mitochondrial dysfunction, including failure to gain chrome enzymes of terminal electron transport and the weight, short stature, fatigue, respiratory problems enzymes of the citric acid cycle, fatty acid oxidation, and oxidative phosphorylation. They are responsible for con 0159) Mitochondrial defects have been linked to Alzhe imer's, Parkinson's, diabetes, autism, and the aging process. verting nutrients into energy as well as many other special Other disease associated with mitochondrial dysfunction ized tasks. Mitochondria are complex organelles located in include, LIC (Lethal Infantile Cardio myopathy), Beta virtually all cells of the body. A large degree of their oxidation Defects, COX Deficiency, Mitochondrial Cytopa complexity is due to the fact that over 1000 proteins are thy, Alpers Disease, Barth syndrome, Carnitine-Acyl-Car located in the mitochondria. Thirteen of these proteins are nitine Deficiency, Carnitine Deficiency, Co-Enzyme Q10 encoded by the mitochondrial DNA (mtDNA), while the Deficiency, Complex I Deficiency, Complex II Deficiency, remainder are nuclear-encoded, and imported into the mito Complex III Deficiency, Complex IV Deficiency, Complex chondria. V Deficiency, CPEO, CPT I Deficiency, Glutaric Aciduria 0148. As used herein a “mitochondrial disease or disor Type II, KSS, lactic acidosis, LCAD, LCHAD, Leigh Dis der” refers to any illness resulting from a deficiency of any ease, LHON, Luft Disease, MAD, MCA, MELAS, MERRF, mitochondrial-located protein which is involved in energy mitochondrial DNA depletion, Mitochondrial Encephalo metabolism. Therefore, deficiencies of the respiratory (elec path, MNGIE, NARP Pearson Syndrome, Pyruvate Car tron transport) chain, either resulting from a deficiency in boxylase Deficiency, Pyruvate Dehydrogenase Deficiency, none or more of the mitochondrial or nuclear-encoded SCAD, SCHAD and VLCAD. proteins, are mitochondrial disorders. Also, by definition, 0.160 Alpers Disease, or Progressive Infantile Poliodys disorders of the fatty acid (beta) oxidation, Krebs cycle and trophy, includes symptoms Such as , dementia, spas pyruvate dehydrogenase complex deficiency are mitochon ticity, blindness, liver dysfunction, and cerebral degenera drial disorders. Although theses disorders may be geneti tion. (Luft; The development of mitochondrial medicine. cally dissimilar, all disorders contemplated by the present Proceedings of the National Academy of Sciences of the invention are similar in that they result in an energy deficient United States of America, 1994; 91 (19); 8731-8). State. 0.161 Barth syndrome or LIC (Lethal Infantile Cardio 014.9 There is no one identifying feature of mitochon myopathy) is an X-linked recessive disorder the symptoms drial disease. Subjects can have combinations of problems of which include skeletal myopathy, cardiomyopathy, short whose onset may occur from before birth to late adult life. stature, and neutropenia. (Christodoulou, Barth syndrome: Mitochondrial diseases should be considered in the differ clinical observations and genetic linkage studies. American ential diagnosis when there are these unexplained features, Journal of Medical Genetics, 1994: 50(3): 255-64). especially when these occur in combination. Mitochondria disease and disorders can affect multiple organs, resulting in 0162 Carnitine-Acyl-Carnitine Deficiency is an autoso a vast array of symptoms. Symptoms which may affect the mal recessive disorder, the symptoms of which are seizures, brain include, developmental delays, mental retardation, apnea, bradycardia, , lethargy, coma, enlarged liver, dementia, seizures, neuro-psychiatric disturbances, atypical limb weakness, myoglobin in the urine, Reye-like symptoms cerebral palsy, migraines, strokes. triggered by fasting. 0.163 Carnitine Deficiency is an autosomal recessive 0150. Symptoms which affect the nervous system may disease, the symptoms of which include Cardio myopathy, include, weakness (which may be intermittent), neuropathic failure to thrive, and altered consciousness or coma, some pain, absent reflexes, gastrointestinal problem (gastroeso times . phogeal reflux, delayed gastric emptying, constipation, pseudo-obstruction), fainting, absent or excessive Sweating 0.164 Co-Enzyme Q10 Deficiency is most likely an auto resulting in temperature regulation problems. Somal recessive disease, the symptoms of which include Encephalo myopathy, mental retardation, exercise intoler 0151. Symptoms which affect muscle may include, weak ance, ragged-red fibers, and recurrent myoglobin in the ness, hypotonia, cramping and muscle pain. U1. US 2007/0021589 A1 Jan. 25, 2007

0165 Complex I Deficiency or NADH dehydrogenase 0171 CPT I Deficiency is an autosomal recessive disease (NADH-CoQ reductase) deficiency is an autosomal disease, and includes symptoms such as enlarged liver and recurrent the symptoms of which are classified by three major forms: Reye-like episodes triggered by fasting or illnesses. (1) fatal infantile multisystem disorder, characterized by 0172 CPT II Deficiency is an autosomal recessive dis developmental delay, muscle weakness, heart disease, con ease, the symptoms of which include exercise intolerance, genital lactic acidosis, and respiratory failure; (2) myopathy fasting intolerance, muscle pain, muscle stiffness, and myo beginning in childhood or in adult life, manifesting as globin in the urine and in infants, Reye-like syndrome, exercise intolerance or weakness. Elevated lactic acid com enlarged liver, hypoglycemia, enlarged heart and cardiac mon; and (3) mitochondrial encephalo myopathy (including arrhythmia. MELAS), which may begin in childhood or adult life and consists of variable combinations of symptoms and signs, 0173 KSS or Kearns-Sayre Syndrome, in most cases is including ophthalmoplegia, seizures, dementia, ataxia, hear caused by large mitochondria DNA deletions. Symptoms ing loss, pigmentary retinopathy, sensory neuropathy, and associated with KSS include progressive external ophthal uncontrollable movements. In addition, this disorder may moplegia, pigmentary retinopathy, heart block, and high cause Leigh Syndrome. cerebrospinal protein. 0166 Complex II Deficiency or Succinate dehydroge 0.174 Lactic Acidosis is associated with the accumulation nase deficiency, the symptoms of which include encephalo of lactic acid due to its production exceeding its use. Chronic myopathy and various manifestations, including failure to lactic acidosis is a common symptom of mitochondrial thrive, developmental delay, hyoptonia, lethargy, respiratory disease. failure, ataxia, myoclonus and lactic acidosis. May also 0.175 LCAD or Long-Chain Acyl-CoA Dehydrongenase cause Leigh Syndrome. Deficiency, is an autosomal recessive disorder, which causes 0167 Complex III Deficiency or Ubiquinone-cyto a fatal syndrome, in infants, typified by failure to thrive, chrome c oxidoreductase deficiency, symptoms of which are enlarged liver, enlarged heart, metabolicencephalopathy and categorized in four major forms: (1) fatal infantile encephal hypotonia. myopathy, congenital lactic acidosis, hypotonia, dystrophic 0176 LCHAD is an autosomal recessive disorder, char posturing, seizures, and coma. Ragged-red fibers common; acterized by symptoms such as encephalopathy, liver dys (2) encephalomyopathies of later onset (childhood to adult function, cardiomyopathy, and myopathy. Also pigmentary life): various combinations of weakness, short stature, retinopathy and peripheral neuropathy. ataxia, dementia, hearing loss, sensory neuropathy, pigmen tary retinopathy, and pyramidal signs. Ragged-red fibers 0.177 Leigh Disease or Syndrome or Subacute Necrotiz common. Possible lactic acidosis; (3) myopathy, with exer ing Encephalomyelopathy is characterized by symptoms cise intolerance evolving into fixed weakness. Ragged-red Such as Seizures, hypotonia, fatigue, nystagmus, poor fibers common. Possible lactic acidosis; and (4) infantile reflexes, eating and Swallowing difficulties, breathing prob histiocytoid cardio myopathy. lem and poor motor function, 0.178 LHON or Leber Hereditary Optic Neuropathy is 0168 Complex IV Deficiency or Cytochrome c oxidase caused by mitochondrial DNA point mutations, including deficiency is caused by a defect in Complex IV of the G14459A, among others. Symptoms associated with LHON respiratory chain, the symptoms of which can be categorized include primarily blindness in young men. Less common in two major forms: (1) encephalo myopathy, which is symptoms include mild dementia, ataxia, Spasticity, periph typically normal for the first 6 to 12 months of life and then eral neuropathy and heart conduction defects. show developmental regression, ataxia, lactic acidosis, optic atrophy, ophthalmoplegia, nystagmus, dystonia, pyramidal 0.179 Luft Disease is characterized by symptoms such as signs, respiratory problems and frequent seizures; and (2) hypermetabolism, with fever, heat intolerance, profuse per myopathy: Two main variants: (a) Fatal infantile myopathy: spiration, polyphagia, polydipsia, ragged-red fibers, and may begin soon after birth and accompanied by hypotonia, resting tachycardia. In addition to exercise intolerance with weakness, lactic acidosis, ragged-red fibers, respiratory fail mild weakness. ure, and kidney problems: and b) Benign infantile myopa 0180 MAD or Glutaric Aciduria Type II or multiple thy: may begin soon after birth and accompanied by hypo Acyl-CoA Dehydrogenase Deficiency is caused by defects tonia, weakness, lactic acidosis, ragged-red fibers, of the flavoproteins responsible for transferring electrons respiratory problems, but (if the child survives) followed by (ETF or ETF-dehydrogenase) therefor affecting the function spontaneous improvement. of all six ETF-funneling acyl-CoA dehydrogenases. 0169 Complex V Deficiency or ATP synthase deficiency 0181 MCAD or Medium-Chain Acyl-CoA Dehydronge includes symptoms Such as slow, progressive myopathy. nase Deficiency is an autosomal recessive disorder, which 0170 CPEO or Chronic Progressive External Ophthal afflicts infants or young children with episodes of encepha moplegia Syndrome includes symptoms such as visual lopathy, enlarged and fatty degeneration of the liver, and low myopathy, retinitis pigmentosa, dysfunction of the central carnitine in the blood. nervous system. It is caused by single mitochondrial DNA 0182 MELAS or Mitochondrial Encephalo myopathy deletions, with Mitochondrial DNA point mutation, A3243G Lactic Acidosis and Strokelike Episodes is caused by mito being the most common (Luft; The development of mito chondrial DNA point mutations, the most common of which chondrial medicine. Review; Proceedings of the National is A3243G. It is characterized by symptoms: Short statue, Academy of Sciences of the United States of America, 1994; seizures, stroke-like episodes with focused neurological 91 (19); 8731-8). deficits, recurrent headaches, cognitive regression, disease US 2007/0021589 A1 Jan. 25, 2007 progression ragged-red fibers (Koo, et. al.; Mitochondrial 0194 VLCAD or Very Long-Chain Acyl-CoA Dehy encephalo myopathy, lactic acidosis, stroke-like episodes drongenase Deficiency is an autosomal recessive disorder, (MELAS): clinical, radiological, pathological, and genetic characterized by various manifestations, ranging from fatal observations. Annals of Neurology, 1993 : 34(1): 25-32). infantile encephalopathy to recurrent myoglobin in the 0183 MERRF or Myoclonic Epilepsy and Ragged-Red urine, similar to the myopathic form of CPT II deficiency. Fiber Disease is caused by the mitochondrial DNA point 0.195. In addition, other diseases and disorders which can mutations A8344G and T8356C. Its symptoms include myo be treated using the methods of the present invention clonus, epilepsy, progressive ataxia, muscle weakness and include, without being limited to, A-Beta-Lipoproteinemia, degeneration, deafness and dementia (Luft; The develop A-V. A Beta-2-Microglobulin Amyloidosis, A-T. A1AD, ment of mitochondrial medicine; Proceedings of the A1AT, Aagenaes, Aarskog syndrome, Aarskog-Scott Syn National Academy of Sciences of the United States of drome, Aase-Smith syndrome, Aase Syndrome, AAT, Abder America, 1994; 91 (19); 8731-8). halden-Kaufmann-Lignac Syndrome, Abdominal Muscle 0184 There are three forms of mitochondrial DNA Deficiency Syndrome, Abdominal Wall Defect, Abdominal Depletion. These include: (1) congenital myopathy: Neona Epilepsy, Abdominal Migraine, Abductor Spasmodic Dys tal weakness, hypotonia requiring assisted ventilation, pos phonia, Abductor Spastic Dysphonia, Abercrombie Syn sible renal dysfunction. Severe lactic acidosis. Prominent drome, blepharon-Macrostomia Syndrome, ABS, Absence ragged-red fibers. Death due to respiratory failure usually of HPRT. Absence of Corpus Callosum Schinzel Typ, occurs prior to one year of age; (2) infantile myopathy: Absence Defect of Limbs Scalp and Skull, Absence of Following normal early development until one year old, Menstruation Primar, Absence of HGPRT. Absorptive weakness appears and worsens rapidly, causing respiratory Hyperoxaluriaor Enteric, Abt-Letterer-Siwe Disease, failure and death typically within a few years; and (3) ACADL, ACADM Deficiency, ACADM, ACADS, Acan hepatopathy, enlarged liver and intractable liver failure, thocytosis-Neurologic Disorder, Acanthocytosis, Acantholy myopathy. Severe lactic acidosis. Death is typical within the sis Bullosa, Acanthosis Nigricans, Acanthosis Bullosa, first year. Acanthosis Nigricans With Insulin Resistance Type A, Acan thosis Nigricans With Insulin Resistance Type B, Acanthotic 0185. Mitochondrial Encephalopathy, also includes Nevus, Acatalasemia, Acatalasia, ACC. Accessory Atrioven Encephalo myopathy and Encephalomyelopathy. tricular Pathways. Accessory Atrioventricular Pathways, 0186 MNGIE or Myoneurogastointestinal Disorder and Acephaly, ACF with Cardiac Defects, Achalasia, Achard Encephalopathy, include symptoms such as progressive Thiers Syndrome, ACHARD (Marfan variant), Achard’s syndrome, Acholuric Jaundice, Achondrogenesis, Achon external ophthalmoplegia, limb weakness, peripheral neur drogenesis Type IV. Achondrogenesis Type III, Achondro opathy, digestive tract disorders, leukodystrophy, lactic aci plasia, Achondroplasia Tarda, Achondroplastic Dwarfism, dosis and ragged red fibers. Achoo Syndrome, Achromat, Achromatope, Achromatopic, 0187 NARP or Neuropathy, Ataxia, and Retinitis Pig Achromatopsia, Achromic Nevi, Acid Ceramidase Defi mentosa is caused by mitochondrial DNA point mutations in ciency, Acid Maltase Deficiency, Acid Beta-glucosidase genes associated with Complex V, including T8993G, (also Deficiency, Acidemia Methylmalonic, Acidemia Propionic, T8993C by some researchers). Leigh Syndrome may result Acidemia with Episodic Ataxia and Weakness, Acidosis, if the percentage of mutation is high enough. Aclasis Tarsoepiphyseal, ACM, Acoustic Neurilemoma, 0188 Pearson Syndrome is characterized by symptoms Acoustic Neuroma, ACPS with Leg Hypoplasia, ACPS II, associated with bone marrow and pancreas dysfunction. It is ACPS IV, ACPS III, Acquired Aphasia with Convulsive caused by single mitochondrial DNA deletions. Inheritance Disorder. Acquired Brown Syndrome. Acquired Epileptic is usually sporadic. Aphasia, Acquired Factor XIII Deficiency, Acquired Form of ACC (caused by infection while still in womb). Acquired 0189 Those who survive infancy usually develop Hyperoxaluria, Acquired Hypogammaglobulinemia, Kearns-Sayre Syndrome. Acquired Immunodeficiency Syndrome (AIDS), Acquired Iron Overload, Acquired Lipodystrophy, Acquired Partial 0.190 Pyruvate Carboxylase Deficiency is an autosomal Lipodystrophy, Acquired Wandering Spleen, ACR, Acral recessive disorder, the symptoms of which include lactic Dysostosis with Facial and Genital Abnormalities, Acro acidosis, hypoglycemia, severe retardation, failure to thrive, Renal, Acrocallosal Syndrome Schinzel Type, Acrocepha in addition to seizures and spasticity. losyndactyly, AcrocephaloSyndactyly Type I, Acrocephalo 0191 Pyruvate Dehydrogenase Deficiency is character Syndactyly Type I Subtype I, Acrocephalopolysyndactyly ized by symptoms such as lactic acidosis, ataxia, pyruvic Type II, Acrocephalopolysyndactyly Type III, Acrocepha acidosis, spinal and cerebellar degeneration. Less common lopolysyndactyly Type IV. Acrocephalosyndactyly V (ACS5 symptoms include agenesis of the corpus callosum and or ACS V) Subtype I, Acrocephaly Skull Asymmetry and lesions in the basal ganglia, cerebelum, and brain stem, Mild Syndactyly, Acrocephaly, Acrochondrohyperplasia, growth delay, hypotonia, seizures and polyneuropathy. Acrodermatitis Enteropathica, Acrodysostosis, Acrodystro 0192 SCAD or Short-Chain Acyl-CoA Dehydrogenase phic Neuropathy, Acrofacial Dysostosis Nager Type, Acro Deficiency, is an autosomal recessive disorder characterized facial Dysostosis Postaxial Type, Acrofacial Dysostosis by symptoms such as failure to thrive, developmental delay Type Genee-Wiedep, Acrogeria Familial, Acromegaly, and hypoglycemia. Acromelalgia Hereditary, Acromesomelic Dysplasia, Acromesomelic Dwarfism, Acromicric Skeletal Dysplasia, 0193 SCHAD is an autosomal recessive disorder, char Acromicric Dysplasia, Acroosteolysis with Osteoporosis acterized by encephalopathy and possibly liver disease or and Changes in Skull and Mandible, Acroosteolysis, Acro cardio myopathy. paresthesia, ACS I, ACS Type II, ACS Type III, ACS, ACS3, US 2007/0021589 A1 Jan. 25, 2007

ACTH Deficiency, Action Myoclonus, Acute Brachial Neu drome, Alexander's Disease, Alexanders Disease, Algodys ritis Syndrome, Acute Brachial Radiculitis Syndrome, Acute trophy, Algoneurodystrophy, , Alkaptonuric Cerebral Gaucher Disease, Acute Cholangitis, Acute Dis , Alkyl DHAP synthase deficiency, Allan-Hern seminated Encephalomyeloradiculopathy, Acute Dissemi don-Dudley Syndrome, Allan-Herndon Syndrome, Allan nated Histiocytosis-X, Acute Hemorrhagic Polioencephali Hemdon-Dudley Mental Retardation, Allergic Granuloma tis, Acute Idiopathic Polyneuritis, Acute Immune-Mediation tous Antitis, Allergic Granulomatous Angiitis of Cronkhite Polyneuritis, Acute Infantile Pelizaeus-Merzbacher Brain Canada, Alobar Holoprosencephaly, Alopecia Areata, Sclerosis, Acute Intermittant Porphyria, Acute Porphyrias, Alopecia Celsi, Alopecia Cicatrisata, Alopecia Circum Acute Sarcoidosis, Acute Shoulder Neuritis, Acute Toxic scripta, Alopecia-Poliosis-Uveitis-Vitiligo-Deafness-Cuta Epidermolysis, Acyl-CoA Dehydrogenase Deficiency Long neous-Uveo-O, Alopecia Seminuniversalis, Alopecia Tota Chain, Acyl-CoA Dehydrogenase Deficiency Short-Chain, lis, Alopecia Universalis, Alpers Disease, Alpers Diff-use Acyl-CoA Dihydroxyacetone Acyltransferase, Acyl-coen Degeneration of Cerebral Gray Matter with Hepatic Cirrho Zyme A Oxidase Deficiency, ADA, ADA Deficiency, Adam sis, Alpers Progressive Infantile Poliodystrophy, Alpha-1- Complex, Adamantiades-Behcet’s Syndrome, Adamanti Antitrypsin Deficiency, Alpha-1 4 Glucosidase Deficiency, noma, Adams Oliver Syndrome, Adaptive Colitis, ADD Alpha-Galactosidase A Deficiency, Alpha-Galactosidase B combined type, ADD, Addison Disease with Cerebral Scle Deficiency, Alpha High-Density Lipoprotein Deficieny, rosis. Addison's Anemia, Addison's Disease, Addison Alpha-L-Fucosidase Deficiency Fucosidosis Type 3, Alpha Biermer Anemia, Addison-Schilder Disease, Addisonian GalNAc Deficiency Schindler Type, Alphalipoproteinemia, Pernicious Anemia, Adducted Thumbs-Mental Retardation, Alpha Mannosidosis, Alpha-N-Acetylgalactosaminidase Adductor Spasmodic Dysphonia, Adductor Spastic Dyspho Deficiency Schindler Type, Alpha-NAGADeficiency Schin nia, Adenoma Associated Virilism of Older Women, dler Type, Alpha-Neuraminidase Deficiency, Alpha-Thalas Adenomatosis of the Colon and Rectum, Adenomatous semia/mental retardation syndrome non-deletion type, polyposis of the Colon, Adenomatous Polyposis Familial, Alphalipoproteinemia, Alport Syndrome, ALS, Alstroems Adenosine Deaminase Deficiency, AdenyloSuccinase defi Syndrome, Alstroem, Alstrom Syndrome. Alternating ciency, ADHD predominantly hyperactive-impulsive type, Hemiplegia Syndrome. Alternating Hemiplegia of Child ADHD predominantly inattentive type, ADHD, Adhesive hood, Alzheimer's Disease, Amaurotic Familial Idiocy, Arachnoiditis, Adie Syndrome, Adie's Syndrome, Adie's Amaurotic Familial Idiocy Adult, Amaurotic Familial Infan Tonic Pupil, Adie's Pupil, Adipogenital Retinitis Pigmen tile Idiocy, Ambiguous Genitalia, AMC, AMD, Ameloblas tosa Polydactyly, Adipogenital-Retinitis Pigmentosa Syn toma, Amelogenesis Imperfecta, Amenorrhea-Galactorrhea drome, Adiposa Dolorosa, Adiposis Dolorosa, Adiposogeni Nonpuerperal, Amenorrhea-Galactorrhea-FSH Decrease tal Dystrophy, Adolescent , ADPKD, Adrenal Syndrome, Amenorrhea, Amino Acid Disorders, Aminoaci Cortex Adenoma, Adrenal Disease, Adrenal Hyperfunction duria-Osteomalacia-Hyperphosphaturia Syndrome, AMN, resulting from Pituitary ACTH Excess, Adrenal Hypoplasia, Amniocentesis, Amniotic Bands, Amniotic Band Syndrome, Adrenal Insufficiency, Adrenal Neoplasm, Adrenal Virilism, Amniotic Band Disruption Complex, Amniotic Band Adreno-Retinitis Pigmentosa-Polydactyly Syndrome, Sequence, Amniotic Rupture Sequence, Amputation Con Adrenocortical Insufficiency, Adrenocortical Hypofunction, genital, AMS, Amsterdam Dwarf Syndrome de Lange, Adrenocorticotropic Hormone Deficiency Isolated, Adreno Amylo-1 6-Glucosidase Deficiency, Amyloid Arthropathy genital Syndrome, Adrenoleukodystrophy, Adrenomyelo of Chronic Hemodialysis, Amyloid Corneal Dystrophy, neuropathy, Adreno-Retinitis Pigmentosa-Polydactyly Syn Amyloid Polyneuropathy, Amyloidosis, Amyloidosis of drome, Adult Cystinosis, Adult Dermatomyositis, Adult Familial Mediterranean Fever, Amylopectinosis, Amyopla Hypophosphatasia, Adult Macula Lutea Retinae Degenera sia Congenita, Amyotrophic Lateral Sclerosis, Amyotrophic tion, Adult Onset ALD, Adult-Onset Ceroidosis, Adult Onset Lateral Sclerosis, Amyotrophic Lateral Sclerosis-Polyglu Medullary Cystic Disease. Adult Onset Pernicious Anemia, cosan Bodies, AN, AN 1, AN 2, Anal Atresia, Anal Mem Adult Onset Schindler Disease, Adult-Onset Subacute brane, Anal Rectal Malformations, Anal Stenosis, Analine Necrotizing Encephalomyelopathy, Adult Polycystic Kidney 60 Amyloidosis, Analphalipoproteinemia, Analrectal, Anal Disease, Adult Onset Medullary Cystic Disease, Adynlosuc rectal, Anaplastic Astrocytoma, Andersen Disease, Ander cinate Lyase Deficiency, AE, AEC Syndrome, AFD, Afi son-Fabry Disease, Andersen Glycogenosis, Anderson-War brinogenemia, African Siderosis, AGA, Aganglionic Mega burg Syndrome, Andre Syndrome, Andre Syndrome Type II, colon, Age Related Macular Degeneration, Agenesis of Androgen Insensitivity, Androgen Insensitivity Syndrome Commissura Magna Cerebri, Agenesis of Corpus Callosum, Partial, Androgen Insensitivity Syndrome Partial, Andro Agenesis of Corpus Callosum-Infantile Spasms-Ocular genic Steroids, Anemia Autoimmune Hemolytic, Anemia Anomalies, Agenesis of Corpus Callosum and Chorioretinal Blackfan Diamond, Anemia, Congenital, Triphalangeal Abnormality, Agenesis of Corpus Callosum-Chorioretinitis Thumb Syndrome, Anemia Hemolytic Cold Antibody, Ane Abnormality, Aggressive mastocytosis, Agnosis Primary, mia Hemolytic with PGK Deficiency, Anemia Pernicious, AGRTriad, AGU, Agyria, Agyria-pachygria-band spectrum, Anencephaly, Angelman Syndrome, Angio-Osteohypertro AHC, AHD, AHDS, AHF Deficiency, AHG Deficiency, phy Syndrome, Angiofollicular Lymph Node Hyperplasia, AHO, Ahumada Del Castillo, Aicardi Syndrome, AIED, Angiohemophilia, Angiokeratoma Corporis, Angiokeratoma AIMP, AIP. AIS, Akinetic , ALA-D Porphyria, Alac Corporis Difflisum, Angiokeratoma Diffuse, Angiomatosis tasia, Alagille Syndrome, Aland Island Eye Disease Retina, Angiomatous Lymphoid, Angioneurotic Edema (X-Linked), Alaninuria, Albers-Schonberg Disease, Albi Hereditary, Anhidrotic Ectodermal Dysplasia, Anhidrotic nism, Albinismus, Albinoidism, Albright Hereditary Osteod X-Linked Ectodermal Dysplasias, Aniridia, Aniridia-Am ystrophy, Alcaptonuria, Alcohol-Related Birth Defects, biguous Genitalia-Mental Retardation, Aniridia Associated Alcoholic Embryopathy, Ald, ALD, ALD, Aldosterone, with Mental Retardation, Aniridia-Cerebellar Ataxia-Mental Aldosteronism With Normal Blood Pressure, Aldrich Syn Deficiency, Aniridia Partial-Cerebellar Ataxia-Mental Retar US 2007/0021589 A1 Jan. 25, 2007

dation, Aniridia Partial-Cerebellar Ataxia-Oligophrenia, Block, Atrioventricular Canal Defect, Atrioventricular Sep Aniridia Type I, Aniridia Type II, Aniridia-Wilms Tumor tal Defect, Atrophia Bulborum Hereditaria, Atrophic Beri Association, Aniridia-Wilms Tumor-Gonadoblastoma, beri, Atrophy Olivopontocerebellar, Attention Deficit Dis Ankyloblepharon-Ectodermal Defects-Cleft Lip/Palate, order, Attention Deficit Hyperactivity Disorder, Attentuated Ankylosing Spondylitis, Annular groves, Anodontia, Adenomatous Polyposis Coli, Atypical Amyloidosis, Atypi Anodontia Vera, Anomalous Trichromasy, Anomalous Dys cal Hyperphenylalaninemia, Auditory Canal Atresia, plasia of Dentin, Coronal Dentin Dysplasia, Anomic Apha Auriculotemporal Syndrome, Autism, Autism Asperger's sia, Anophthalmia, Anorectal, Anorectal Malformations, Type, Autism Dementia Ataxia and Loss of Purposeful Hand Anosmia, Anterior Bowing of the Legs with Dwarfism, Use, Autism Infantile Autism, Autoimmune Addison's Dis Anterior Membrane Corneal Dystrophy, Anti-Convulsant ease, Autoimmune Hemolytic Anemia, Autoimmune Hepa Syndrome, Anti-Epstein-Barr Virus Nuclear Antigen titis, Autoimmune-Polyendocrinopathy-Candidias, Autoim (EBNA) Antibody Deficiency, Antibody Deficiency, Anti mune Polyglandular Disease Type I, Autosomal Dominant body Deficiency with near normal Immunoglobulins, Anti Albinism, Autosomal Dominant Compelling Heliooph hemophilic Factor Deficiency, Antihemophilic Globulin thalmic Outburst Syndrome, Autosomal Dominant Desmin Deficiency, Antiphospholipid Syndrome, Antiphospholipid Distal myopathy with Late Onset, Autosomal Dominant Antibody Syndrome, Antithrombin III Deficiency, Anti EDS, Autosomal Dominant Emery-Dreifuss Muscular Dys thrombin III Deficiency Classical (Type I), Antitrypsin Defi trophy, Autosomal Dominant Keratoconus, Autosomal ciency, Antley-Bixler Syndrome, Antoni’s Palsy, Anxietas Dominant Pelizaeus-Merzbacher Brain Sclerosis, Autoso Tibialis, Aorta Arch Syndrome, Aortic and Mitral Atresia mal Dominant Polycystic Kidney Disease, Autosomal with Hypoplasic Left Heart Syndrome, Aortic Stenosis, Dominant Spinocerebellar Degeneration, Autosomal Reces Aparoschisis, APC, APECED Syndrome, Apert Syndrome, sive Agammaglobulinemia, Autosomal Recessive Centro Aperts, Aphasia, Aplasia AXialis Extracorticales Congenital, nuclear myopathy, Autosomal Recessive Conradi-Huner Aplasia Cutis Congenita, Aplasia Cutis Congenita with mann Syndrome, Autosomal Recessive EDS, Autosomal Terminal Transverse Limb Defects, Aplastic Anemia, Aplas Recessive Emery-Dreifuss Muscular Dystrophy, Autosomal tic Anemia with Congenital Anomalies, APLS, Apnea, Recessive Forms of , Autosomal Recessive Appalachian Type Amyloidosis, Apple Peel Syndrome, Inheritance Agenesis of Corpus Callosum, Autosomal Apraxia, Apraxia Buccofacial, Apraxia Constructional, Recessive Keratoconus, Autosomal Recessive Polycystic Apraxia Ideational, Apraxia Ideokinetic, Apraxia Ideomotor, Kidney Disease, Autosomal Recessive Severe Combined Apraxia Motor, Apraxia Oculomotor, APS, Arachnitis, Immunodeficiency, AV, AVM, AVSD, AWTA, Axilla Arachnodactyly Contractural Beals Type, Arachnodactyly, Abscess, AXonal Neuropathy Giant, Azorean Neurologic Arachnoid Cysts, Arachnoiditis Ossificans, Arachnoiditis, Disease, B-K Mole Syndrome, Babinski-Froelich Syn Aran-Duchenne, Aran-Duchenne Muscular Atrophy, drome. BADS, Baillarger's Syndrome, Balkan Disease, Aregenerative Anemia, Arginase Deficiency, , Baller-Gerold Syndrome, Ballooning Mitral Valve, Balo Arginino Succinase Deficiency, Argininosuccinase Defi Disease Concentric Sclerosis, Baltic Myoclonus Epilepsy, ciency, Argininosuccinate Lyase Deficiency, Argininosuc Bannayan-Zonana syndrome (BZS), Bannayan-Riley-Ru cinic Acid Lyase-ASL, Argininosuccinic Acid Synthetase valcaba syndrome, Banti’s Disease, Bardet-Biedl Syn Deficiency, Argininosuccinic Aciduria, Argonz-Del Castillo drome, Bare Lymphocyte Syndrome, Barlow's syndrome, Syndrome, Arhinencephaly, Armenian Syndrome, Arnold Barraquer-Simons Disease, Barrett Esophagus, Barrett Chiari Malformation, Arnold-Chiari Syndrome, ARPKD, Ulcer, Barth Syndrome, Bartter's Syndrome, Basal Cell Arrhythmic Myoclonus, Arrhythmogenic Right Ventricular Nevus Syndrome, Basedow Disease, Bassen-KomZweig Dysplasia, Arteriohepatic Dysplasia, Arteriovenous Malfor Syndrome, Batten Disease, Batten-Mayou Syndrome, Bat mation, Arteriovenous Malformation of the Brain, Arteritis ten-Spielmeyer-Vogt's Disease, Batten Turner Syndrome, Giant Cell, Arthritis, Arthritis Urethritica, Arthro-Dento Batten Turner Type Congenital myopathy, Batten-Vogt Syn Osteodysplasia, Arthro-Ophthalmopathy, Arthrochalasis drome, BBB Syndrome, BBB Syndrome (Opitz), BBB Multiplex Congenita, Arthrogryposis Multiplex Congenita, Syndrome, BBBG Syndrome, BCKD Deficiency, BD, Arthrogryposis Multiplex Congenita, Distal, Type IIA, BDLS, BE, Beals Syndrome, Beals Syndrome, Beals-Hecht ARVD, Arylsulfatase-B Deficiency, AS, ASA Deficiency, Syndrome, Bean Syndrome, BEB, Bechterew Syndrome, Ascending Paralysis, ASD, Atrioseptal Defects, ASH, Ash Becker Disease. Becker Muscular Dystrophy, Becker ermans Syndrome, Ashkenazi Type Amyloidosis, ASL Defi Nevus, Beckwith Wiedemann Syndrome. Beckwith-Syn ciency, Aspartylglucosarninuria, Aspartylglycosaminuria, drome, Begnez-Cesar's Syndrome, Behcet’s syndrome, Asperger's Syndrome, Asperger's Type Autism, Asphyxiat Behcet’s Disease, Behr 1, Behr 2, Bell's Palsy, Benign ing Thoracic Dysplasia, Asplenia Syndrome, ASS Defi Acanthosis Nigricans, Benign Astrocytoma, Benign Cranial ciency, Asthma, Astrocytoma Grade I (Benign), Astrocy Nerve Tumors, Benign Cystinosis, Benign Essential Ble toma Grade II (Benign), Asymmetric Crying Facies with pharospasm, Benign Essential Tremor, Benign Familial Cardiac Defects, Asymmetrical septal hypertrophy, Asymp Hematuria, Benign Focal Amyotrophy, Benign Focal Amyo tomatic Callosal Agenesis, AT, AT Im Deficiency, AT III trophy of ALS, Benign Hydrocephalus, Benign Hypermo Variant IA, AT III Variant lb., AT3, Ataxia, Ataxia Telang bility Syndrome, Benign Keratosis Nigricans, Benign Par iectasia, Ataxia with Lactic Acidosis Type II, Ataxia Cere oxysmal Peritonitis, Benign Recurrent Hematuria, Benign bral Palsy, Ataxiadynamia, Ataxiophemia, ATD, Athetoid Recurrent Intrahepatic Cholestasis, Benign Spinal Muscular Cerebral Palsy, Atopic Eczema, Atresia of Esophagus with Atrophy with Hypertrophy of the Calves, Benign Symmetri or without Tracheoesophageal Fistula, Atrial Septal Defects, cal Lipomatosis, Benign Tumors of the Central Nervous Atrial Septal Defect Primum, Atrial and Septal and Small System, Berardinelli-Seip Syndrome, Berger's Disease, Ventricular Septal Defect, Atrial Flutter, Atrial Fibrillation, Beriberi, Berman Syndrome, Bernard-Homer Syndrome, Atriodigital Dysplasia, Atrioseptal Defects, Atrioventricular Bernard-Soulier Syndrome, Besnier Prurigo, Best Disease, US 2007/0021589 A1 Jan. 25, 2007 20

Beta-Alanine-Pyruvate Aminotransferase, Beta-Galactosi cium Pyrophosphate Dihydrate Deposits, Callosal Agenesis dase Deficiency Morquio Syndrome, Beta-Glucuronidase and Ocular Abnormalities, Calves-Hypertrophy of Spinal Deficiency, Beta Oxidation Defects, Beta Thalassemia Muscular Atrophy, Campomelic Dysplasia, Campomelic Major, Beta Thalassemia Minor, Betalipoprotein Deficiency, Dwarfism, Campomelic Syndrome, Camptodactyly-Cleft Bethlem myopathy, Beuren Syndrome, BH4. Deficiency, Palate-Clubfoot, Camptodactyly-Limited Jaw Excursion, Biber-Haab-Dimmer Corneal Dystrophy, Bicuspid Aortic Camptomelic Dwarfism, Camptomelic Syndrome, Camp Valve, Biedl-Bardet, Bifid Cranium, Bifunctional Enzyme tomelic Syndrome Long-Limb Type, Camurati-Engelmann Deficiency, Bilateral Acoustic Neurofibromatosis, Bilateral Disease, Canada-Cronkhite Disease, Canavan disease, Acoustic Neuroma, Bilateral Right-Sidedness Sequence, Canavan's Disease Included, Canavan's Leukodystrophy, Bilateral Renal Agenesis, Bilateral Temporal Lobe Disorder, Cancer, Cancer Family Syndrome Lynch Type, Cantrell Bilious Attacks, Bilirubin Glucuronosyltransferase Defi Syndrome, Cantrell-Haller-Ravich Syndrome, Cantrell Pen ciency Type I, Binder Syndrome, Binswanger's Disease, talogy, Carbamyl Phosphate Synthetase Deficiency, Carbo Binswanger's Encephalopathy, Biotinidase deficiency, Bird hydrate Deficient Glycoprotein Syndrome, Carbohydrate Headed Dwarfism Seckel Type, Birth Defects, Birthmark, Deficient Glycoprotein Syndrome Type Ia, Carbohydrate Bitemporal Forceps Marks Syndrome, Biventricular Fibro Induced Hyperlipemia, Carbohydrate Intolerance of sis, Bjornstad Syndrome, B-K Mole Syndrome, Black Glucose Galactose, Carbon Dioxide Acidosis, Carboxylase Locks-Albinism-Deafness of Sensoneural Type (BADS), Deficiency Multiple, Cardiac-Limb Syndrome, Cardio-au Blackfan-Diamond Anemia, Blennorrheal Idiopathic Arthri ditory Syndrome, Cardioauditory Syndrome of Jervell and tis, Blepharophimosis, Ptosis, Epicanthus Inversus Syn and Lange-Nielsen, Cardiocutaneous Syndrome, Cardio drome, Blepharospasm, Blepharospasm Benign Essential, facial-cutaneous syndrome, Cardiofacial Syndrome Cayler Blepharospasm Oromandibular Dystonia, Blessig Cysts, Type, Cardiomegalia Glycogenica Diffusa, Cardiomyo BLFS, Blindness, Bloch-Siemens Incontinentia Pigmenti pathic Lentiginosis, Cardio myopathy, Cardio myopathy Melanoblastosis Cutis Linearis, Bloch-Siemens-Sulzberger Associated with Desmin Storage myopathy, Cardio myopa Syndrome, Bloch-Sulzberger Syndrome, Blood types, thy Due to Desmin Defect, Cardio myopathy-Neutropenia Blood type A, Blood type B, Blood type AB, Blood type O, Syndrome, Cardiomyopathy-Neutropenia Syndrome Lethal Bloom Syndrome, Bloom-Torre-Mackacek Syndrome, Blue Infantile Cardiomyopathy, Cardiopathic Amyloidosis, Car Rubber Bleb Nevus, Blue Baby, Blue Diaper Syndrome, diospasm, Cardocardiac Syndrome, Caruitine-Acylcarnitine BMD, BOD, BOFS, Bone Tumor-Epidermoid Cyst-Polypo Translocase Deficiency, Carnitine Deficiency and Disorders, sis, Bonnet-Dechaume-Blanc Syndrome, Bonnevie-Ulrich Carnitine Deficiency Primary, Carnitine Deficiency Second Syndrome, Book Syndrome. BOR Syndrome. BOR.J. Borje ary, Carnitine Deficiency Secondary to MCAD Deficiency, son Syndrome, Borjeson-Forssman-Lehmann Syndrome, Carnitine Deficiency Syndrome, Carnitine Pahnitoyl Trans Bowen Syndrome, Bowen-Conradi Syndrome, Bowen-Con ferase I & II (CPT I & II), Carnitine Palmitoyltransferase radi Hutterite, Bowen-Conradi Type Hutterite Syndrome, Deficiency, Carnitine Palmitoyltransferase Deficiency Type Bowman's Layer, BPEI, BPES, Brachial Neuritis, Brachial 1. Carnitine Palmitoyltransferase Deficiency Type 2 benign Neuritis Syndrome, Brachial Plexus Neuritis, Brachial classical muscular form included severe infantile form Plexus-Neuropathy, Brachiocephalic Ischemia, Brachmann included, Carnitine Transport Defect (Primary Carnitine de Lange Syndrome, Brachycephaly, Brachymorphic Type Deficiency), Carnosinase Deficiency, , Caroli Congenital, Bradycardia, Brain Tumors, Brain Tumors Disease, Carpenter syndrome, Carpenters, Cartilage-Hair Benign, Brain Tumors Malignant, Branched Chain Alpha Hypoplasia, Castleman's Disease, Castleman's Disease Ketoacid Dehydrogenase Deficiency, Branched Chain Keto Hyaline Vascular Type, Castleman's Disease Plasma Cell nuria I, Brancher Deficiency, Branchio-Oculo-Facial Syn Type, Castleman Tumor, Cat Eye Syndrome, Cat's Cry drome, Branchio-Oto-Renal Dysplasia, Branchio-Oto-Renal Syndrome, Catalayse deficiency, Cataract-Dental Syn Syndrome, Branchiooculofacial Syndrome, Branchiootic drome, Cataract X-Linked with Hutchinsonian Teeth, Cat Syndrome, Brandt Syndrome, Brandywine Type Dentino echolamine hormones, Catel-Manzke Syndrome, Catel genesis Imperfecta, Brandywine type Dentinogenesis Imper Manzke Type Palatodigital Syndrome, Caudal Dysplasia, fecta, Breast Cancer, BRIC Syndrome, Brittle Bone Disease, Caudal Dysplasia Sequence, Caudal Regression Syndrome, Broad Beta Disease, Broad Thumb Syndrome, Broad Causalgia Syndrome Major, Cavernomas, Cavernous Thumbs and Great Toes Characteristic Facies and Mental Angioma, Cavernous Hemangioma, Cavernous Lymphan Retardation, Broad Thumb-Hallux, Broca's Aphasia, Brocq gioma, Cavernous Malformations, Cayler Syndrome, Duhring Disease, Bronze Diabetes, Bronze Schilder's Dis Cazenave's Vitiligo, CBGD, CBPS, CCA, CCD, CCHS, ease, Brown Albinism, Brown Enamel Hereditary, Brown CCM Syndrome, CCMS, CCO, CD, CDG 1a, CDG1A, Sequard Syndrome, Brown Syndrome, BRRS, Brueghel CDGS Type Ia, CDGS, CDI, CdLS, Celiac Disease, Celiac Syndrome, Bruton's Agammaglobulinemia Common, BS, sprue, Celiac Sprue-Dermatitis, Cellular Immunodeficiency BSS, Buchanan’s Syndrome, Budd's Syndrome, Budd with Purine Nucleoside Phosphorylase Deficiency, Celsus' Chiari Syndrome, Buerger-Gruetz Syndrome, Bulbospinal Vitiligo, Central Apnea, Central Core Disease, Central Dia Muscular Atrophy-X-linked, Bulldog Syndrome, Bullosa betes Insipidus, Central Form Neurofibromatosis, Central Hereditaria, Bullous CIE, Bullous Congenital Ichthyosiform Hypoventilation, Central Sleep Apnea, Centrifugal Lipod Erythroderma, Bullous Ichthyosis, Bullous Pemphigoid, ystrophy, Centronuclear myopathy, CEP, Cephalocele, Burkitt's Lymphoma, Burkitt's Lymphoma African type, Cephalothoracic Lipodystrophy, Ceramide Trihexosidase Burkitt's Lymphoma Non-african type, BWS, Byler's Dis Deficiency, Cerebellar Agenesis, Cerebellar Aplasia, Cer ease, C Syndrome, C1 Esterase Inhibitor Dysfunction Type ebellar Hemiagenesis, Cerebellar Hypoplasia, Cerebellar II Angioedema, C1-INH, C1 Esterase Inhibitor Deficiency Vermis Aplasia, Cerebellar Vermis Agenesis-Hypernea-Epi Type I Angioedema, CINH, Cacchi-Ricci Disease, CAD, sodic Eye Moves-Ataxia-Retardation, Cerebellar Syndrome, CADASIL, CAH, Calcaneal Valgus, Calcaneovalgus, Cal Cerebellarparenchymal Disorder IV. Cerebellomedullary US 2007/0021589 A1 Jan. 25, 2007

Malformation Syndrome, Cerebello-Oculocutaneous 4 Long Arm Deletion, Chromosome 4 Mono Telangiectasia, Cerebelloparenchymal Disorder IV Familial, Somy 4q, Chromosome 4-Monosomy 4q, Chromosome 4 Cerebellopontine Angle Tumor, Cerebral Arachnoiditis, Monosomy Distal 4q, Chromosome 4 Partial Deletion 4p, Cerebral Autosomal Dominant Arteriopathy with Subcorti Chromosome 4, Partial Deletion of the Short Arm, Chro cal Infarcts and Leukodystrophy, Cerebral Beriberi, Cere mosome 4 Partial Monosomy of Distal 4q, Chromosome 4 bral Diplegia, Cerebral Gigantism, Cerebral Malformations Partial Monosomy 4p, Chromosome 4 Partial Trisomy 4 Vascular, Cerebral Palsy, Cerebro-Oculorenal Dystrophy, (q25-qter), Chromosome 4 Partial Trisomy 4 (q26 or q27 Cerebro-Oculo-Facio-Skeletal Syndrome, Cerebrocosto qter), Chromosome 4 Partial Trisomy 4 (q31 or 32-qter), mandibular syndrome, Cerebrohepatorenal Syndrome, Chromosome 4 Partial Trisomy 4p, Chromosome 4 Partial Cerebromacular Degeneration, Cerebromuscular Dystrophy Trisomies 4q2 and 4q3, Chromosome 4 Partial Trisomy Fukuyama Type, Cerebroocular Dysgenesis, Cerebroocular Distal 4, Chromosome 4 Ring, Chromosome 4 4q Terminal Dysplasia-Muscular Dystrophy Syndrome, Cerebrooculofa Deletion Syndrome, Chromosome 4q-Syndrome, Chromo cioskeletal Syndrome, Cerebroretinal Arteriovenous Aneu Some 4q-Syndrome, Chromosome 4 Trisomy 4, Chromo rysm, Cerebroside Lipidosis, Cerebrosidosis, Cerebrotendi some 4 Trisomy 4p, Chromosome 4 XY/47 XXY (Mosiac), nous Xanthomatosis, Cerebrovascular Ferrocalcinosis, Chromosome 5 Monosomy 5p, Chromosome 5, Partial Ceroid-Lipofuscinosis Adult form, Cervical Dystonia, Cer Deletion of the Short Arm Syndrome, Chromosome 5 Tri vical Dystonia, Cervico-Oculo-Acoustic Syndrome, Cervi somy 5p, Chromosome 5 Trisomy 5p Complete (5p11-pter), cal Spinal Stenosis, Cervical Vertebral Fusion, CES, CF, Chromosome 5 Trisomy 5p Partial (5p13 or 14-pter), Chro CFC syndrome, CFIDS, CFND, CGD, CGF, Chalasodermia mosome 5p-Syndrome, Chromosome 6 Partial Trisomy 6q, Generalized, Chanarin Dorfinan Disease, Chanarin Dorfman Chromosome 6 Ring, Chromosome 6 Trisomy 6q2, Chro Syndrome, Chanarin Dorfinan Ichthyosis Syndrome, Chan mosome 7 Monosomy 7p2, Chromosome 7 Partial Deletion dler's Syndrome, Charcot's Disease, Charcot-Marie-Tooth, of Short Arm (7p2-), Chromosome 7 Terminal 7p Deletion Charcot-Marie-Tooth Disease, Charcot-Marie-Tooth Dis del (7) (p21-p22), Chromosome 8 Monosomy 8p2, Chro ease Variant, Charcot-Marie-Tooth-Roussy-Levy Disease, mosome 8 Monosomy 8p21-pter, Chromosome 8 Partial CHARGE Association, Charge Syndrome, CHARGE Syn Deletion (short arm), Chromosome 8 Partial Monosomy drome, Chaund's Ectodermal Dysplasias, Chediak-Higashi 8p2, Chromosome 9 Complete Trisomy 9P, Chromosome 9 Syndrome, Chediak-Steinbrinck-Higashi Syndrome, Cheili Partial Deletion of Short Arm, Chromosome 9 Partial Mono tis Granulomatosa, Cheiloschisis, Chemke Syndrome, somy 9p, Chromosome 9 Partial Monosomy 9p22, Chro Cheney Syndrome, Cherry Red Spot and Myoclonus Syn mosome 9 Partial Monosomy 9p22-pter, Chromosome 9 drome, CHF, CHH, Chiaris Disease, Chiari Malformation I, Partial Trisomy 9P Included, Chromosome 9 Ring, Chro Chiari Malformation, Chiari Type I (Chiari Malformation I). mosome 9 Tetrasomy 9p, Chromosome 9 Tetrasomy 9p Chiari Type II (Chiari Malformation II), Chiari I Syndrome, Mosaicism, Chromosome 9 Trisomy 9p. (Multiple Variants), Chiari-Budd Syndrome, Chiari-Frommel Syndrome, Chiari Chromosome 9 Trisomy 9 (pter-p21 to q32) Included, Chro Malformation II, CHILD Syndrome, CHILD Ichthyosis mosome 9 Trisomy Mosaic, Chromosome 9 Trisomy Syndrome, CHILD Syndrome Ichthyosis, Childhood Adre Mosaic, Chromosome 10 Distal Trisomy 10q, Chromosome noleukodystrophy, Childhood Dermatomyositis, Childhood 10 Monosomy, Chromosome 10 Monosomy 10p, Chromo onset Dystonia, Childhood Cyclic Vomiting, Childhood some 10, Partial Deletion (short arm), Choromsome 10, Giant Axonal Neuropathy, Childhood Hypophosphatasia, 10p-Partial, Chromosome 10 Partial Trisomy 10q24-qter, Childhood Muscular Dystrophy, CHN. Cholestasis, Chromosome 10 Trisomy 10q2, Partial Monosomy of Long Cholestasis Hereditary Norwegian Type, Cholestasis Intra Arm of Chromosome 11, Chromosome 11 Partial Mono hepatic, Cholestasis Neonatal, Cholestasis of Oral Contra somy 11q, Chromosome 11 Partial Trisomy, Chromosome ceptive Users, Cholestasis with Peripheral Pulmonary 11 Partial Trisomy 11q13-qter, Chromosome 11 Partial Stenosis, Cholestasis of Pregnancy, Cholesterol Desmolase Trisomy 11q21-qter, Chromosome 11 Partial Trisomy Deficiency, Chondrodysplasia Punctata, Chondrodystrophia 11q23-qter, Chromosome 11q, Partial Trisomy, Chromosome Calcificans Congenita, Chondrodystrophia Fetalis, Chon 12 Isochromosome 12p Mosaic, Chromosome 13 Partial drodystrophic Myotonia, Chondrodystrophy, Chondrodys Monosomy 13q, Chromosome 13, Partial Monosomy of the trophy with Clubfeet, Chondrodystrophy Epiphyseal, Chon Long Arm, Chromosome 14 Ring, Chromosome 14 Tri drodystrophy Hyperplastic Form, Chondroectodermal somy, Chromosome 15 Distal Trisomy 15q, Chromosome Dysplasias, Chondrogenesis Imperfecta, Chondrohystro r15, Chromosome 15 Ring, Chromosome 15 Trisomy 15q2. phia, Chondroosteodystrophy, Choreoacanthocytosis, Chromosome 15q Partial Duplication Syndrome, Chromo Chorionic Villi Sampling, Chorioretinal Anomalies, Chori some 17 Interstitial Deletion 17p, Chromosome 18 Long oretinal Anomalies with ACC, Chorireninal Coloboma-Jou Arm Deletion Syndrome, Chromosome 18 Monosomy 18p. bert Syndrome, Choroidal Sclerosis, Choroideremia, Chromosome 18 Monosomy 18Q, Chromosome 18 Ring, Chotzen Syndrome, Christ-Siemens-Touraine Syndrome, Chromosome 18 Tetrasomy 18p, Chromosome 18q-Syn Christ-Siemans-Touraine Syndrome, Christmas Disease, drome, Chromosome 21 Mosaic 21 Syndrome, Chromo Christmas Tree Syndrome, Chromosome 3 Deletion of Dis Some 21 Ring, Chromosome 21 Translocation 21 Syndrome, tal 3p, Chromosome 3 Distal 3p Monosomy, Chromosome Chromosome 22 Inverted Duplication (22pter-22q11), 3-Distal 3q2 Duplication, Chromosome 3-Distal 3q2 Tri Chromosome 22 Partial Trisomy (22pter-22q11), Chromo Somy, Chromosome 3 Monosomy 3p2, Chromosome 3q some 22 Ring, Chromosome 22 Trisomy Mosaic, Chromo Partial Duplication Syndrome, Chromosome 3q, Partial Tri some 48 XXYY. Chromosome 48 XXXY, Chromosome r15, somy Syndrome, Chromosome 3-Trisomy 3q2, Chromo Chromosomal Triplication, Chromosome Triplication, some 4 Deletion 4q31-qter Syndrome, Chromosome 4 Dele Chromosome Triploidy Syndrome, Chromosome X, Chro tion 4q32-qter Syndrome, Chromosome 4 Deletion 4q33 mosome XXY. Chronic Acholuric Jaundice, Chronic Adhe qter Syndrome, Chromosome 4 Long Arm Deletion, sive Arachnoiditis, Chronic Adrenocortical Insufficiency, US 2007/0021589 A1 Jan. 25, 2007 22

Chronic Cavernositis, Chronic Congenital Aregenerative Degeneration, Cone-Rod Degeneration Progressive, Cone Anemia, Chronic Dysphagocytosis, Chronic Familial Dystrophy, Cone-Rod Dystrophy, Confluent Reticular Pap Granulomatosis, Chronic Familial Icterus, Chronic Fatigue illomatosis, Congenital with low PK Kinetics, Congenital Immune Dysfunction Syndrome (CFIDS), Chronic Granu Absence of Abdominal Muscles, Congenital Absence of the lomatous Disease, Chronic Guillain-Barre Syndrome, Thymus and Parathyroids, Congenital Achromia, Congenital Chronic Idiopathic Jaundice, Chronic Idiopathic Polyneuri Addison's Disease, Congenital Adrenal Hyperplasia, Con tis (CIP), Chronic Inflammatory Demyelinating Polyneur genital Adreneal Hyperplasia, Congenital Afibrinogenemia, opathy, Chronic Inflammatory Demyelinating Polyradiculo Congenital Alveolar HypoVentilation, Congenital Anemia of neuropathy, Chronic Motor Tic, Chronic Mucocutaneous Newborn, Congenital Bilateral Persylvian Syndrome, Con Candidiasis, Chronic Multiple Tics, Chronic Non-Specific genital Brown Syndrome, Congenital Cardiovascular Ulcerative Colitis, Chronic Obliterative Cholangitis, Defects, Congenital Central Hypoventilation Syndrome, Chronic Peptic Ulcer and Esophagitis Syndrome, Chronic Congenital Cerebral Palsy, Congenital Cervical Synostosis, Progressive Chorea, Chronic Progressive External Ophthal Congenital Clasped Thunb with Mental Retardation, Con moplegia Syndrome, Chronic Progressive External Ophthal genital Contractural Arachnodactyly, Congenital Contrac moplegia and myopathy, Chronic Progressive External Oph tures Multiple with Arachnodactyly, Congenital Cyanosis, thalmoplegia with Ragged Red Fibers, Chronic Relapsing Congenital Defect of the Skull and Scalp, Congenital Dila Polyneuropathy, Chronic Sarcoidosis, Chronic Spasmodic tation of Intrahepatic Bile Duct, Congenital Dysmyelinating Dysphonia, Chronic Vomiting in Childhood, CHS, Churg Neuropathy, Congenital Dysphagocytosis, Congenital Dys Strauss Syndrome, Cicatricial Pemphigoid, CIP, Cirrhosis plastic Angiectasia, Congenital Erythropoietic Porphyria, Congenital Pigmentary, Cirrhosis, Cistinuria, , Congenital Factor XIII Deficiency, Congenital Failure of CJD. Classic Schindler Disease, Classic Type Pfeiffer Syn Autonomic Control of Respiration, Congenital Familial drome, Classical Maple Syrup Urine Disease, Classical Nonhemolytic Jaundice Type I, Congenital Familial Pro Hemophilia, Classical Form Cockayne Syndrome Type I tracted Diarrhea, Congenital Form Cockayne Syndrome (Type A), Classical Leigh's Disease, Classical Phenylketo Type II (Type B), Congenital Generalized Fibromatosis, nuria, Classical X-Linked Pelizaeus-Merzbacher Brain Scle Congenital German Measles, Congenital Giant AXonal Neu rosis, CLE, Cleft Lip/Palate Mucous Cysts Lower Lip PP ropathy, Congenital Heart Block, Congenital Heart Defects, Digital and Genital Anomalies, Cleft Lip-Palate Blepharo Congenital Hemidysplasia with Ichthyosis Erythroderma phimosis Lagophthalmos and Hypertelorism, Cleft Lip/Pal and Limb Defects, Congenital Hemolytic Jaundice, Con ate with Abnormal Thumbs and Microcephaly, Cleft palate genital Hemolytic Anemia, Congenital Hepatic Fibrosis, joint contractures-dandy walker malformations, Cleft Palate Congenital Hereditary Corneal Dystrophy, Congenital and Cleft Lip, Cleidocranial Dysplasia w/Micrognathia, Hereditary Lymphedema, Congenital Hyperchondroplasia, Absent Thumbs, & Distal Aphalangia, Cleidocranial Dys Congenital Hypomyelinating Polyneuropathy, Congenital ostosis, Cleidocranial Dysplasia, Click murmur syndrome, Hypomyelination Neuropathy, Congenital Hypomyelina CLN1, Clonic Spasmodic, Cloustons Syndrome, Clubfoot, tion, Congenital Hypomyelination (Onion Bulb) Polyneur CMDI, CMM, CMT, CMTC, CMTX, COA Syndrome, opathy, Congenital Ichthyosiform Erytiroderma, Congenital Coarctation of the aorta, Coats Disease, Cobblestone dys Keratoconus, Congenital Lactic Acidosis, Congenital Lac plasia, Cochin Jewish Disorder, Cockayne Syndrome, COD tose Intolerance, Congenital Lipodystrophy, Congenital MD Syndrome, COD, Coffin Lowry Syndrome, Coffin Syn Liver Cirrhosis, Congenital Lobar Emphysema, Congenital drome, Coffin Siris Syndrome, COFS Syndrome, Cogan Localized Emphysema, Congenital Macroglossia, Congeni Corneal Dystrophy, Cogan Reese Syndrome, Cohen Syn tal Medullary Stenosis, Congenital Megacolon, Congenital drome, Cold Agglutinin Disease, Cold Antibody Disease, Melanocytic Nevus, Congenital Mesodermal Dysmorphod Cold Antibody Hemolytic Anemia, Colitis Ulcerative, Coli yStrophy, Congenital Mesodermal Dystrophy, Congenital tis Gravis, Colitis Ulcerative Chronic Non-Specific Ulcer MicroVillus Atrophy, Congenital Multiple Arthrogryposis, ative Colitis, Collodion Baby, Coloboma Heart Defects Congenital Myotonic Dystrophy, Congenital Neuropathy Atresia of the Choanae Retardation of Growth and Devel caused by Hypomyelination, Congenital Pancytopenia, Con opment Genital and Urinary Anomalies and Ear Anomalies, genital Pernicious Anemia, Congenital Pernicious Anemia Coloboma, Colonic Neurosis, Color blindness, Colour due to Defect of Intrinsic Factor, Congenital Pernicious blindness, Colpocephaly, Columnar-Like Esophagus, Com Anemia due to Defect of Intrinsic Factor, Congenital Pig bined Cone-Rod Degeneration, Combined Immunodefi mentary Cirrhosis, Congenital Porphyria, Congenital Proxi ciency with Immunoglobulins, Combined Mesoectodermal mal myopathy Associated with Desmin Storage myopathy, Dysplasia, Common Variable Hypogammaglobulinemia, Congenital Pulmonary Emphysema, Congenital Pure Red Common Variable Immunodeficiency, Common Ventricle, Cell Anemia, Congenital Pure Red Cell Aplasia, Congenital Communicating Hydrocephalus, Complete Absense of Retinal Blindness, Congenital Retinal Cyst, Congenital Hypoxanthine-Guanine Phosphoribosyltranferase, Com Retinitis Pigmentosa, Congenital Retinoschisis, Congenital plete Atrioventricular Septal Defect, Complement Compo Rod Disease, Congenital Rubella Syndrome, Congenital nent 1 Inhibitor Deficiciency, Complement Component C1 Scalp Defects with Distal Limb Reduction Anomalies, Con Regulatory Component Deficiency, Complete Heart Block, genital Sensory Neuropathy, Congenital SMA with arthro Complex Carbohydrate Intolerance, Complex Regional Pain gryposis, Congenital Spherocytic Anemia, Congenital Syndrome, Complex V ATP Synthase Deficiency, Complex Spondyloepiphyseal Dysplasia, Congenital Tethered Cervi I, Complex I NADH dehydrogenase deficiency, Complex II, cal Spinal Cord Syndrome, Congenital Tyrosinosis, Con Complex II Succinate dehydrogenase deficiency, Complex genital Varicella Syndrome, Congenital Vascular Cavernous III, Complex III Ubiquinone-cytochrome c oxidoreductase Malformations, Congenital Vascular Veils in the Retina, deficiency, Complex IV, Complex IV Cytochrome c oxidase Congenital Word Blindness, Congenital Wandering Spleen deficiency, Complex IV Deficiency, Complex V. Cone-Rod (Pediatric), Congestive Cardio myopathy, Conical Cornea, US 2007/0021589 A1 Jan. 25, 2007

Conjugated Hyperbilirubinemia, Conjunctivitis, Conjunc Oxidase Deficiency, D.C., Dacryosialoadenopathy, Dacryo tivitis Ligneous, Conjunctivo-Urethro-Synovial Syndrome, sialoadenopathia, Dalpro, Dalton, Daltonism, Danbolt Conn's Syndrome, Connective Tissue Disease, Conradi Dis Cross Syndrome, Dancing Eyes-Dancing Feet Syndrome, ease, Conradi Hunermann Syndrome, Constitutional Aplas Dandy-Walker Syndrome, Dandy-Walker Cyst, Dandy tic Anemia, Constitutional Erythroid Hypoplasia, Constitu Walker Deformity, Dandy Walker Malformation, Danish tional Eczema, Constitutional Liver Dysfunction, Cardiac Type Amyloidosis (Type III), Darier Disease, Constitutional Thrombopathy, Constricting Bands Congeni Davidson's Disease, Davies Disease, DBA, DBS, DC, DD, tal, Constrictive Pericarditis with Dwarfism, Continuous De Barsy Syndrome, De Barsy-Moens-Diercks Syndrome, Muscle Fiber Activity Syndrome, Contractural Arachnodac de Lange Syndrome, De Morsier Syndrome, De Santis tyly, Contractures of Feet Muscle Atrophy and Oculomotor Cacchione Syndrome, de Toni-, Deafness Apraxia, Convulsions, Cooley's anemia, Copper Transport Congenital and Functional Heart Disease, Deafness-Dwarf Disease, Coproporphyria Porphyria Hepatica, Cor Triatria ism-Retinal Atrophy, Deafness-Functional Heart Disease, tum, Cor Triatriatum Sinistrum, Cor Triloculare Biatriatum, Deafness Onychodystrophy Osteodystrophy and Mental Cor Biloculare, Cori Disease, Cornea Dystrophy, Corneal Retardation, Deafness and Pili Torti Bjornstad Type, Deaf Amyloidosis, Corneal Clouding-Cutis Laxa-Mental Retar ness Sensorineural with Imperforate Anus and Hypoplastic dation, Corneal Dystrophy, Cornelia de Lange Syndrome, Thumbs, Debrancher Deficiency, Deciduous Skin, Defect of Coronal Dentine Dysplasia, Coronary Artery Disease, Coro Enterocyte Intrinsic Factor Receptor, Defect in Natural nary Heart Disease, Corpus Callosum Agenesis, Cortical Killer Lymphocytes, Defect of Renal Reabsorption of Car Basal Ganglionic Degeneration, Corticalis Deformaris, Cor nitine, Deficiency of Glycoprotein Neuraminidase, Defi tico-Basal Ganglionic Degeneration (CBGD), Corticobasal ciency of Mitochondrial Respiratory Chain Complex IV. Degeneration, Corticosterone Methloxidase Deficiency Deficiency of Platelet Glycoprotein Ib. Deficiency of Von Type I, Corticosterone Methyloxidase Deficiency Type II, Willebrand Factor Receptor, Deficiency of Short-Chain Cortisol, Costello Syndrome, Cot Death, COVESDEM Syn Acyl-CoA Dehydrogenase (ACADS), Deformity with drome, COX, COX Deficiency, COX Deficiency French Mesomelic Dwarfism, Degenerative Chorea, Degenerative Canadian Type, COX Deficiency Infantile Mitochondrial Lumbar Spinal Stenosis, Degos Disease, Degos-Kohlmeier myopathy de Toni-Fanconi-Debre included, COX Defi Disease, Degos Syndrome, DEH. Dejerine-Roussy Syn ciency Type Benign Infantile Mitochondrial Myopathy, CP, drome, Dejerine Sottas Disease, Deletion 9p Syndrome CPEO, CPEO with myopathy, CPEO with Ragged-Red Partial, Deletion 11q Syndrome Partial, Deletion 13q Syn Fibers, CPPD Familial Form, CPT Deficiency, CPTD, Cra drome Partial, Delleman-Oorthuys Syndrome, Delleman nial Arteritis, Cranial Meningoencephalocele, Cranio-Oro Syndrome, Dementia with Lobar Atrophy and Neuronal Digital Syndrome, Craniocarpotarsal dystrophy, Craniocele, Cytoplasmic Inclusions, Demyelinating Disease, DeMyer Craniodigital Syndrome-Mental Retardation Scott Type, Syndrome, Dentin Dysplasia Coronal, Dentin Dysplasia Craniofacial Dysostosis, Craniofacial Dysostosis-PD Arte Radicular, Dentin Dysplasia Type I, Dentin Dysplasia Type riosus-Hypertrichosis-Hypoplasia of Labia, Craniofrontona II, Dentinogenesis Imperfecta Brandywine type, Dentino sal Dysplasia, Craniometaphyseal Dysplasia, Cranioorodigi genesis Imperfecta Shields Type, Dentinogenesis Imperfecta tal Syndrome, Cranioorodigital Syndrome Type II, Type III, Dento-Oculo-Osseous Dysplasia, Dentooculocuta Craniostenosis Crouzon Type, Craniostenosis, Craniosynos neous Syndrome, IDenys-Drash Syndrome, Depakene, tosis-Choanal Atresia-Radial Humeral Synostosis, Cranio DepakeneTM exposure, Depakote, Depakote Sprinkle, Synostosis-Hypertrichosis-Facial and Other Anomalies, Depigmentation-Gingival Fibromatosis-Microphthalmia, Craniosynostosis Midfacial Hypoplasia and Foot Abnor Dercum Disease, Dermatitis Atopic, Dermatitis Exfoliativa, malities, Craniosynostosis Primary, Craniosynostosis-Ra Dermatitis Herpetiformis, Dermatitis Multiformis, Derma dial Aplasia Syndrome, Craniosynostosis with Radial tochalasia Generalized, Dermatolysis Generalized, Der Defects, Cranium Bifidum, CREST Syndrome, Creutzfeldt matomegaly, Dermatomyositis sine myositis, Dermatomyo Jakob Disease, Cri du Chat Syndrome, Crib Death, Crigler sitis, Derrnatosparaxis, Dermatostomatitis Stevens Johnson Najjar Syndrome Type I, Crohn's Disease, Cronkhite Type, Desbuquois Syndrome, Desmin Storage myopathy, Canada Syndrome, Cross Syndrome, Cross Syndrome, Desquamation of Newborn, Deuteranomaly, Developmental Cross-McKusick-Breen Syndrome, Crouzon, Crouzon Syn Reading Disorder, Developmental Gerstmann Syndrome, drome, Crouzon Craniofacial Dysostosis, Cryoglobulinemia Devergie Disease, Devic Disease, Devic Syndrome, Dex Essential Mixed, Cryptophthalmos-Syndactyly Syndrome, trocardia-Bronchiectasis and Sinusitis, Dextrocardia with Cryptorchidism-Dwarfism-Subnormal Mentality, Crystal Situs Inversus, DGS, DGSX Golabi-Rosen Syndrome line Corneal Dystrophy of Schnyder, CS, CSD, CSID, CSO, Included, DH, DHAP alkyl transferase deficiency, DHBS CST Syndrome, Curly Hair-Ankyloblephanon-Nail Dyspla Deficiency, DHOF, DHPR Deficiency, Diabetes Insipidus, sia, Curschmann-Batten-Steinert Syndrome, Curth Macklin Diabetes Insipidus Diabetes Mellitus Optic Atrophy and Type Ichthyosis Hystric, Curti-Macklin Type, Cushings, Deafness, Diabetes Insipidus Neurohypophyseal, Diabetes Cushing Syndrome, Cushing's m, Cutaneous Malignant Insulin Dependent, Diabetes Mellitus, Diabetes Mellitus Melanoma Hereditary, Cutaneous Porphyrias, Cutis Laxa, Addison's Disease Myxedema, Diabetic Acidosis, Diabetic Cutis Laxa-Growth Deficiency Syndrome, Cutis Marmorata Bearded Woman Syndrome, Diamond-Blackfan Anemia, Telangiectatica Congenita, CVI. CVID, CVS, Cyclic vom Diaphragmatic Apnea, Diaphyseal Aclasis, Diastrophic iting syndrome, Cystic Disease of the Renal Medulla, Cystic Dwarfism, Diastrophic Dysplasia, Diastrophic Nanism Syn Hygroma, Cystic Fibrosis, Cystic Lymphangioma, Cystine drome, Dicarboxylic , Dicarboxylicaciduria Lysine-Arginine-Ornithinuria, Cystine Storage Disease, Caused by Defect in Beta-Oxidation of Fatty Acids, Dicar Cystinosis, , Cystinuria with Dibasic Aminoaci boxylicaciduria due to Defect in Beta-Oxidation of Fatty duria, Cystinuria Type I, Cystinuria Type II, Cystinuria Type Acids, Dicarboxylicaciduria due to MCADH Deficiency, III, Cysts of the Renal Medulla Congenital, Cytochrome C Dichromasy, Dicker-Opitz, DIDMOAD. Diencephalic Syn US 2007/0021589 A1 Jan. 25, 2007 24 drome, Diencephalic Syndrome of Childhood, Diencephalic Bones & Transient Hypocalcemia, Dwarfism Levi’s Type, Syndrome of Emaciation, Dienoyl-CoA Reductase Defi Dwarfism Metatropic, Dwarfism-Onychodysplasia, Dwarf ciency. Diffuse Cerebral Degeneration in Infancy, Diffuse ism-Pericarditis, Dwarfism with Renal Atrophy and Deaf Degenerative Cerebral Disease. Diffuse Idiopathic Skeletal ness, Dwarfism with Rickets, DWM. Dyggve Melchior Hyperostosis, Diffusum-Glycopeptiduria, DiGeorge Syn Clausen Syndrome, Dysautonomia Familial, Dysbetalipo drome, Digital-Oro-Cranio Syndrome, Digito-Oto-Palatal proteinemia Familial, Dyschondrodysplasia with Heman Syndrome, Digito-Oto-Palatal Syndrome Type I, Digito giomas, Dyschondrosteosis, Dyschromatosis Universalis Oto-Palatal Syndrome Type II, Dihydrobiopterin Synthetase Hereditaria, Dysencephalia Splanchinocystica, Dyskeratosis Deficiency, Dihydropteridine Reductase Deficiency, Dihy Congenita, Dyskeratosis Congenita Autosomal Recessive, droxyacetonephosphate synthase, Dilated (Congestive) Car Dyskeratosis Congenita Scoggins Type, Dyskeratosis Con dio myopathy, Dimitri Disease, Diplegia of Cerebral Palsy, genita Syndrome, Dyskeratosis Follicularis Vegetans, Dys Diplo-Y Syndrome, Disaccharidase Deficiency, Disaccha lexia, Dysmyelogenic Leukodystrophy, Dysmyelogenic ride Intolerance I, Discoid Lupus, Discoid Lupus Erythe Leukodystrophy-Megalobare, Dysphonia Spastica, Dyspla matosus, DISH, Disorder of Cornification, Disorder of sia Epiphysialis Punctata, Dysplasia Epiphyseal Cornification Type I, Disorder of Cornification 4, Disorder Hemimelica, Dysplasia of Nails With Hypodontia, Dyspla of Cornification 6, Disorder of Cornification 8, Disorder of sia Cleidocranial, Dysplasia Fibrous, Dysplasia Gigantism Cornification 9 Netherton's Type, Disorder of Cornification Syndromex-Linked, Dysplasia Osteodental, Dysplastic 11 Phytanic Acid Type, Disorder of Cornification 12 Neutral Nevus Syndrome, Dysplastic Nevus Type, Dyssynergia Cer Lipid Storage Type), Disorder of Conification 13, Disorder ebellaris Myoclonica, Dyssynergia Esophagus, Dystonia, of Cornification 14, Disorder of Cornification 14 Tri Dystopia Canthorum, Dystrophia Adiposogenitalis, Dystro chothiodystrophy Type, Disorder of Cornification 15 phia Endothelialis Cornea, Dystrophia Mesodermalis, Dys (Keratitis Deafness Type), Disorder of Cornification 16, trophic Epidermolysis Bullosa, Dystrophy, Asphyxiating Disorder of Cornification 18 Erythrokeratodermia Variabilis Thoracic, Dystrophy Myotonic, E-D Syndrome, Eagle-Bar Type, Disorder of Cornification 19, Disorder of Cornifica rett Syndrome, Eales Retinopathy, Eales Disease, Ear tion 20, Disorder of Cornification 24, Displaced Spleen, Anomalies-Contractures-Dysplasia of Bone with Disseminated Lupus Erythematosus, Disseminated Neuro Kyphoscoliosis, Ear Patella Short Stature Syndrome, Early dermatitis, Disseminated Sclerosis, Distal 11q Monosomy, Constraint Defects, Early Hypercalcemia Syndrome with Distal 11q-Syndrome, Distal Arthrogryposis Multiplex Con Elfin Facie, Early-onset Dystonia, Eaton Lambert Syn genita Type IIA, Distal Arthrogryposis Multiplex Congenita drome, EB, Ebstein's anomaly, EBV Susceptibility (EBVS), Type IIA, Distal Arthrogryposis Type IIA, Distal Arthrogry EBVS, ECD, ECPSG, Ectodermal Dysplasias, Ectodermal posis Type 2A, Distal Duplication 6q Distal Duplication Dysplasia Anhidrotic with Cleft Lip and Cleft Palate, Ecto 10q, Dup(10q) Syndrome, Distal Duplication 15q Distal dermal Dysplasia-Exocrine Pancreatic Insufficiency, Ecto Monosomy 9p, Distal Trisomy 6q Distal Trisomy 10q dermal Dysplasia Rapp-Hodgkin type, Ectodermal and Syndrome, Distal Trisomy 11q, Divalproex, DJS, DKC, Mesodermal Dysplasia Congenital, Ectodermal and Meso DLE, DLPIII, DM, DMC Syndrome, DMC Disease, DMD, dermal Dysplasia with Osseous Involvement, Ectodermosis DNS Hereditary, DOC I, DOC2, DOC4, DOC 6 (Harlequin Erosiva Pluriorificialis, Ectopia Lentis, Ectopia Vesicae, Type), DOC 8 Curth-Macklin Type, DOC 11 Phytanic Acid Ectopic ACTH Syndrome, Ectopic Adrenocorticotropic Type, DOC 12 (Neutral Lipid Storage Type), DOC 13, DOC Hormone Syndrome, Ectopic Anus, Ectrodactilia of the 14, DOC 14 Trichothiodystrophy Type, DOC 15 (Keratitis Hand, Ectrodactyly, Ectrodactyly-Ectodermal Dysplasia Deafness Type), DOC 16, DOC 16 Unilateral Hemidyspla Clefting Syndrome, Ectrodactyly Ectodermal Dysplasias sia Type, DOC 18, DOC 19, DOC 20, DOC 24, Dohle's Clefting Syndrome, Ectrodactyly Ectodermal Dysplasia Bodies-Myelopathy, Dolichospondylic Dysplasia, Dolicho Cleft Lip/Cleft Palate, Eczema, Eczema-Thrombocytope Stenomelia, DolichoStenomelia Syndrome, Dominant Type nia-Immunodeficiency Syndrome, EDA, EDMD, EDS, EDS Kenny-Caffe Syndrome, Dominant Type Myotonia Con Arterial-Ecchymotic Type, EDS Arthrochalasia, EDS Clas genita, Donahue Syndrome, Donath-Landsteiner Hemolytic sic Severe Form, EDS Dysfibronectinemic, EDS Gravis Anemia, Donath-Landsteiner Syndrome, DOOR Syndrome, Type, EDS Hypermobility, EDS Kyphoscoliotic, EDS DOORS Syndrome, Dopa-responsive Dystonia (DRD), Kyphoscoliosis, EDS Mitis Type, EDS Ocular-Scoliotic, Dorfman Chanarin Syndrome, Dowling-Meara Syndrome, EDS Progeroid, EDS Periodontosis, EDS Vascular, EEC Down Syndrome, DR Syndrome, Drash Syndrome, DRD, Syndrome, EFE, EHBA, EHK, Ehlers Danlos Syndrome, Dreifuss-Emery Type Muscular Dystrophy with Contrac Ehlers-Danlos syndrome, Ehlers Danlos IX, Eisenmenger tures, Dressler Syndrome, Drifting Spleen, Drug-induced Complex, Eisenmenger's complex, Eiseminenger Disease, Acanthosis Nigricans, Drug-induced Lupus Erythematosus, Eisenmenger Reaction, Eisenmenger Syndrome, Ekbom Drug-related Adrenal Insufficiency, Drummond's Syn Syndrome, Ekman-Lobstein Disease, Ektrodactyly of the drome, Dry Beriberi, Dry Eye, DTD, Duane's Retraction Hand, EKV, Elastin fiber disorders, Elastorrhexis General Syndrome, Duane Syndrome, Duane Syndrome Type IA 1B ized, Elastosis Dystrophica Syndrome, Elective Mutism and 1C, Duane Syndrome Type 2A 2B and 2C, Duane (obsolete), Elective Mutism, Electrocardiogram (ECG or Syndrome Type 3A 3B and 3C, Dubin Johnson Syndrome, EKG), Electron Transfer Flavoprotein (ETF) Dehydroge Dubowitz Syndrome, Duchenne, Duchenne Muscular Dys nase Deficiency: (GAII & MADD), Electrophysiologic trophy, Duchenne's Paralysis, Duhring's Disease, Duncan study (EPS), Elephant Nails From Birth, Elephantiasis Con Disease, Duncan's Disease, Duodenal Atresia, Duodenal genita Angiomatosa, Hemangiectatic Hypertrophy, Elfin Stenosis, Duodenitis, Duplication 4p Syndrome, Duplica Facies with Hypercalcemia, Ellis-van Creveld Syndrome, tion 6q Partial, Dupuy's Syndrome, Dupuytren’s Contrac Ellis Van Creveld Syndrome, Embryoma Kidney, Embryo ture, Dutch-Kennedy Syndrome, Dwarfism, Dwarfism Cam nal Adenomyosarcoma Kidney, Embryonal Carcinosarcoma pomelic, Dwarfism Cortical Thickening of the Tubular Kidney, Embryonal Mixed Tumor Kidney, EMC, Emery US 2007/0021589 A1 Jan. 25, 2007

Dreyfus Muscular Dystrophy, Emery-Dreifuss Muscular Faciopalatoosseous Syndrome Type II, Facioscapulo Dystrophy, Emery-Dreifuss Syndrome, EMF, EMG Syn humeral muscular dystrophy, Factitious Hypoglycemia, Fac drome, Empty Sella Syndrome, Encephalitis Periaxialis Dif tor VIII Deficiency, Factor IX Deficiency, Factor XI Defi flusa, Encephalitis Periaxialis Concentrica, Encephalocele, ciency, Factor XII deficiency, Factor XIII Deficiency, Fahr Encephalofacial Angiomatosis, Encephalopathy, Encephal Disease, Fahr's Disease, Failure of Secretion Gastric Intrin otrigeminal Angiomatosis, Enchondromatosis with Multiple sic Factor, Fairbank Disease, Fallot's Tetralogy, Familial Cavernous Hemangiomas, Endemic Polyneuritis, Endocar Acrogeria, Familial Acromicria, Familial Adenomatous dial Cushion Defect, Endocardial Cushion Defects, Colon Polyposis, Familial Adenomatous Polyposis with Endocardial Dysplasia, Endocardial Fibroelastosis (EFE). Extraintestinal Manifestations, Familial Alobar Holoprosen Endogenous Hypertriglyceridemia, Endolymphatic cephaly, Familial Alpha-Lipoprotein Deficiency, Familial Hydrops, Endometrial Growths, Endometriosis, Endomyo Amyotrophic Chorea with Acanthocytosis, Familial cardial Fibrosis, Endothelial Corneal Dystrophy Congenital, Arrhythmic Myoclonus, Familial Articular Chondrocalcino Endothelial Epithelial Corneal Dystrophy, Endothelium, sis, Familial Atypical Mole-Malignant Melanoma Syn Engelmann Disease, Enlarged Tongue, Enterocolitis, drome, Familial Broad Beta Disease, Familial Calcium Enterocyte Cobalamin Malabsorption, Eosinophia Syn Gout, Familial Calcium Pyrophosphate Arthropathy, Famil drome, Eosinophilic Cellulitis, Eosinophilic Fasciitis, Eosi ial Chronic Obstructive Lung Disease, Familial Continuous nophilic Granuloma, Eosinophilic Syndrome, Epidermal Skin Peeling, Familial Cutaneous Amyloidosis, Familial Nevus Syndrome, Epidermolysis Bullosa, Epidermolysis Dysproteinemia, Familial Emphysema, Familial Enteropa Bullosa Acquisita, Epidermolysis Bullosa Hereditaria, Epi thy MicroVillus, Familial Foveal Retinoschisis, Familial dermolysis Bullosa Letalias, Epidermolysis Hereditaria Hibernation Syndrome, Familial High Cholesterol, Familial Tarda, Epidermolytic Hyperkeratosis, Epidermolytic Hyper Hemochromatosis, Familial High Blood Cholesterol, Famil keratosis (Bullous CIE), Epilepsia Procursiva, Epilepsy, ial High-Density Lipoprotein Deficiency, Familial High Epinephrine, Epiphyseal Changes and High Myopia, Epi Serum Cholesterol, Familial Hyperlipidema, Familial Hypo physeal Osteochondroma Benign, Epiphysealis Hemimelica proteinemia with Lymphangietatic Enteropathy, Familial Dysplasia, Episodic-Abnormal Eye Movement, Epithelial Jaundice, Familial Juvenile Nephronophtisis-Associated Basement Membrane Corneal Dystrophy, Epithelial Corneal Ocular Anomaly, Familial Lichen Amyloidosis (Type IX), Dystrophy of Meesmann Juvenile, Epitheliomatosis Multi Familial Lumbar Stenosis, Familial Lymphedema Praecox, plex with Nevus, Epithelium, Epival, EPS, Epstein-Barr Familial Mediterranean Fever, Familial Multiple Polyposis, Virus-Induced Lymphoproliferative Disease in Males, Erb Familial Nuchal Bleb, Familial Paroxysmal Polyserositis, Goldflam syndrome, Erdheim Chester Disease, Erythema Familial Polyposis Coli, Familial Primary Pulmonary Multiforme Exudativum; Erythema Polymorphe Stevens Hypertension, Familial Renal Glycosuria, Familial Splenic Johnson Type, Erythroblastophthisis, Erythroblastosis Feta Anemia, Familial Startle Disease, Familial Visceral Amy lis, Erythroblastosis Neonatorum, Erythroblastotic Anemia loidosis (Type VIII), FAMMM, FANCA, FANCB, FANCC, of Childhood, Erythrocyte Phosphoglycerate Kinase Defi FANCD, FANCE, Fanconi Panmyelopathy, Fanconi Pancy ciency, Erythrogenesis Imperfecta, Erythrokeratodermia topenia, Fanconi II, Fanconi's Anemia, Fanconi's Anemia Progressiva Symmetrica, Erythrokeratodermia Progressiva Type I, Fanconi's Anemia Complementation Group, Fanco Symmetrica Ichthyosis, Erythrokeratodermia Variabilis, ni's Anemia Complementation Group A, Fanconi's Anemia Erythrokeratodermia Variabilis Type, Erythrokeratolysis Complementation Group B, Fanconi's Anemia Complemen Hiemalis, Erythropoietic Porphyrias, Erythropoietic Por tation Group C, Fanconi's Anemia Complementation Group phyria, Escobar Syndrome, Esophageal Atresia, Esophageal D. Fanconi's Anemia Complementation Group E, Fanconi's Aperistalsis, Esophagitis-Peptic Ulcer, Esophagus Atresia Anemia Complementation Group G, Fanconi's Anemia and/or Tracheoesophageal Fistula, Essential Familial Hyper Complementation Group H, Fanconi's Anemia Estren lipemia, Essential Fructosuria, Essential Hematuria, Essen Dameshek Variant, FANF, FANG, FANH, FAP, FAPG, tial Hemorrhagic Thrombocythemia, Essential Mixed Cryo Farber's Disease, Farber's Lipogranulomatosis, FAS, Fast globulinemia, Essential Moschowitz Disease, Essential ing Hypoglycemia, Fat-Induced Hyperlipemia, Fatal Granu Thrombocythemia, Essential Thrombocytopenia, Essential lomatous Disease of Childhood, Fatty Oxidation Disorders, Thrombocytosis, Essential Tremor, Esterase Inhibitor Defi Fatty Liver with Encephalopathy, FAV, FCH, FCMD, FCS ciency, Estren-Dameshek variant of Fanconi Anemia, Estro Syndrome, FD, FDH, Febrile Mucocutaneous Syndrome gen-related Cholestasis, ET, ETF, Ethylmalonic Adipicaci Stevens Johnson Type, Febrile Neutrophilic Dermatosis duria, Eulenburg Disease, pc, EVCS, Exaggerated Startle Acute, Febrile Seizures, Feinberg's syndrome, Feissinger Reaction, EXencephaly, Exogenous Hypertriglyceridemia, Leroy-Reiter Syndrome, Female Pseudo-Turner Syndrome, Exomphalos-Macroglossia-Gigantism Syndrom, Exoph Femoral Dysgenesis Bilateral-Robin Anomaly, Femoral thalmic Goiter, Expanded Rubella Syndrome, Exstrophy of Dysgenesis Bilateral, Femoral Facial Syndrome, Femoral the Bladder, EXT, External Chondromatosis Syndrome, Hypoplasia-Unusual Facies Syndrome, Fetal Alcohol Syn Extrahepatic Biliary Atresia, Extramedullary Plasmacy drome, Fetal Anti-Convulsant Syndrome, Fetal Cystic toma, Exudative Retinitis, Eye Retraction Syndrome, FA1, Hygroma, Fetal Effects of Alcohol, Fetal Effects of Chick FAA, Fabry Disease, FAC, FACB, FACD, FACE, FACF, enpox, Fetal Effects of Thalidomide, Fetal Effects of Vari FACG, FACH, Facial Nerve Palsy, Facial Paralysis, Facial cella Zoster Virus, Fetal Endomyocardial Fibrosis, Fetal Ectodermal Dysplasias, Facial Ectodermal Dysplasia, Facio Face Syndrome, Fetal Iritis Syndrome, Fetal Transfusion Scapulo-Humeral Dystrophy, Facio-Auriculo-Vertebral Syndrome, Fetal Valproate Syndrome, Fetal Valproic Acid Spectrum, Facio-cardio-cutaneous syndrome, Facio-Fronto Exposure Syndrome, Fetal Varicefla Infection, Fetal Vari Nasal Dysplasia, Faciocutaneoskeletal Syndrome, Facio cella Zoster Syndrome, FFDD Type II, FG Syndrome, digitogenital syndrome, Faciogenital dysplasia, Faciogeni FGDY, FHS, Fibrin Stabilizing Factor Deficiency, Fibrinase topopliteal Syndrome, Faciopalatoosseous Syndrome, Deficiency, Fibrinoid Degeneration of Astrocytes, Fibrinoid US 2007/0021589 A1 Jan. 25, 2007 26

Leukodystrophy, Fibrinoligase Deficiency, Fibroblastoma hidrosis, Generalized Lipofuscinosis, Generalized Myasthe Perineural, Fibrocystic Disease of Pancreas, Fibrodysplasia nia Gravis, Generalized Myotonia, Generalized Sporadic Ossificans Progressiva, Fibroelastic Endocarditis, Fibromy Neuromytonia, Genetic Disorders, Genital Defects, Genital algia, Fibromyalgia-Fibromyositis, Fibromyositis, Fibrosing and Urinary Tract Defects, Gerstmann Syndrome, Gerst Cholangitis, Fibrositis, Fibrous Ankylosis of Multiple mann Tetrad, GHBP, GHD, GHR, Giant AXonal Disease, Joints, Fibrous Cavernositis, Fibrous Dysplasia, Fibrous Giant AXonal Neuropathy, Giant Benign Lymphoma, Giant Plaques of the Penis, Fibrous Sclerosis of the Penis, Fickler Cell Glioblastoma Astrocytoma, Giant Cell Arteritis, Giant Winkler Type, Fiedler Disease, Fifth Digit Syndrome, Fil Cell Disease of the Liver, Giant Cell Hepatitis, Giant Cell of ippi Syndrome, Finnish Type Amyloidosis (Type V). First Newborns Cirrhosis, Giant Cyst of the Retina, Giant Lymph Degree Congenital Heart Block, First and Second Branchial Node Hyperplasia, Giant Platelet Syndrome Hereditary, Arch Syndrome, Fischer's Syndrome, Fish Odor Syndrome, Giant Tongue, gic Macular Dystrophy, Gilbert's Disease, Fissured Tongue, Flat Adenoma Syndrome, Flatau-Schilder Gilbert Syndrome, Gilbert-Dreyfus Syndrome, Gilbert Disease, Flavin Containing Monooxygenase 2, Floating Lereboullet Syndrome, Gilford Syndrome, Gilles de la Beta Disease, Floating-Harbor Syndrome, Floating Spleen, Tourette's syndrome, Gillespie Syndrome, Gingival Fibro Floppy Infant Syndrome, Floppy Valve Syndrome, Fluent matosis-Abnormal Fingers Nails Nose Ear Splenomegaly, aphasia, FMD, FMF, FMO Adult Liver Form, FMO2, FND, GLADeficiency, GLA, GLB1, Glioma Retina, Global apha Focal Dermal Dysplasia Syndrome, Focal Dermal Hypopla sia, Globoid Leukodystrophy, Glossoptosis Micrognathia sia, Focal Dermato-Phalangeal Dysplasia, Focal Dystonia, and Cleft Palate, Glucocerebrosidase deficiency, Glucocer Focal Epilepsy, Focal Facial Dermal Dysplasia Type II, ebrosidosis, Glucose-6-Phosphate Dehydrogenase Defi Focal Neuromyotonia, FODH, Folling Syndrome, Fong ciency, Glucose-6-Phosphate Tranport Defect, Glucose-6- Disease, FOP, Forbes Disease, Forbes-Albright Syndrome, Phospate Translocase Deficiency, Glucose-G-Phosphatase Forestier's Disease, Forsius-Eriksson Syndrome Deficiency, Glucose-Galactose Malabsorption, Glucosyl (X-Linked), Fothergill Disease. Fountain Syndrome, Foveal Ceramide Lipidosis, Glutaric Aciduria I, Glutaric Acidemia Dystrophy Progressive, FPO Syndrome Type II, FPO, Frac I, Glutaric Acidemia II, Glutaric Aciduria II, Glutaric Aci caro Type Achondrogenesis (Type IB), Fragile X syndrome, duria Type II, Glutaric Aciduria Type III, Glutaricacidemia Franceschetti-Zwalen-Klein Syndrome, Francois Dysceph I, Glutaricacidemia II, Glutaricaciduria I, Glutaricaciduria aly Syndrome, Francois-Neetens Speckled Dystrophy, II, Glutaricaciduria Type IIA, Glutaricaciduria Type IIB, Flecked Comeal Dystrophy, Fraser Syndrome, FRAXA, Glutaryl-CoA Dehydrogenase Deficiency, Glutaurate-As FRDA, Fredrickson Type I Hyperlipoproteinemia, Freeman partate Transport Defect, Gluten-Sensitive Enteropathy, Sheldon Syndrome, Freire-Maia Syndrome, Frey's Syn Glycogen Disease of Muscle Type VII, Glycogen Storage drome, Friedreich's Ataxia, Friedreich's Disease, Frie Disease I, Glycogen Storage Disease III, Glycogen Storage dreich's Tabes, FRNS, Froelich's Syndrome. Frommel Disease IV. Glycogen Storage Disease Type V. Glycogen Chiari Syndrome. Frommel-Chiari Syndrome Lactation Storage Disease VI, Glycogen Storage Disease VII, Glyco Uterus Atrophy. Frontodigital Syndrome. Frontofacionasal gen Storage Disease VIII, Glycogen Storage Disease Type Dysostosis, Frontofacionasal Dysplasia, Frontonasal Dys II, Glycogen Storage Disease-Type II, Glycogenosis, Gly plasia, Frontonasal Dysplasia with Coronal Craniosynosto cogenosis Type I, Glycogenosis Type IA, Glycogenosis sis, Fructose-1-Phosphate Aldolase Deficiency, Fructoseria, Type IB, Glycogenosis Type II, Glycogenosis Type II, Fructosuria, Fryns Syndrome, FSH, FSHD, FSS, Fuchs Glycogenosis Type III, Glycogenosis Type IV. Glycogenosis Dystrophy, Fucosidosis Type 1, Fucosidosis Type 2, Fucosi Type V. Glycogenosis Type VI, Glycogenosis Type VII, dosis Type 3, Fukuhara Syndrome, Fukuyama Disease, CGlycogenosis Type VIII, Glycolic Aciduria, Glycolipid Fukuyama Type Muscular Dystrophy, Fumarylacetoacetase Lipidosis, GM2 Gangliosidosis Type 1, GM2 Gangliosidosis deficiency, Furrowed Tongue, G Syndrome, G6PD Defi Type 1, GNPTA, Goitrous Autoimmune Thyroiditis, Gold ciency, G6PD, GA I, GA IIB, GA IIA, GA II, GAII & enhar Syndrome, Goldenhar-Gorlin Syndrome, Goldsc MADD, Galactorrhea-Amenorrhea Syndrome Nonpuer heider's Disease, Goltz Syndrome, Goltz-Gorlin Syndrome, peral, Galactorrhea-Amenorrhea without Pregnancy, Galac Gonadal Dysgenesis 45 X, Gonadal Dysgenesis XO, tosamine-6-Sulfatase Deficiency, Galactose-1-Phosphate Goniodysgenesis-Hypodontia, Goodman Syndrome, Good Uridyl Transferase Deficiency, Galactosemia, GALB Defi man, Goodpasture Syndrome, Gordon Syndrome, Gorlin’s ciency, Galloway-Mowat Syndrome, Galloway Syndrome, Syndrome, Gorlin-Chaudhry-Moss Syndrome, Gottron GALT Deficiency, Gammaglobulin Deficiency, GAN, Gan Erythrokeratodermia Congenitalis Progressiva Symmetrica, glioside Neuraminidase Deficiency, Ganglioside Sialidase Gottron’s Syndrome, Gougerot-Carteaud Syndrome, Grand Deficiency, Gangliosidosis GM1 Type 1, Gangliosidosis Mal Epilepsy, Granular Type Corneal Dystrophy, Granulo GM2 Type 2, Gangliosidosis Beta Hexosaminidase B matous Arteritis, Granulomatous Colitis, Granulomatous Defeciency, Gardner Syndrome, Gargoylism, Garies-Mason Dermatitis with Eosinophilia, Granulomatous Ileitis, Graves Syndrome, Gasser Syndrome, Gastric Intrinsic Factor Fail Disease, Graves Hyperthyroidism, Graves Disease, Greig ure of Secretion, Enterocyte Cobalamin, Gastrinoma, Gas Cephalopolysyndactyly Syndrome, Groenouw Type I Cor tritis, Gastroesophageal Laceration-Hemorrhage, Gas neal Dystrophy, Groenouw Type II Corneal Dystrophy, trointestinal Polyposis and Ectodermal Changes, Gronblad-Strandberg Syndrome, Grotton Syndrome, Gastroschisis, Gaucher Disease, Gaucher-Schlagenhaufer, Growth Hormone Receptor Deficiency, Growth Hormone Gayet-Wernicke Syndrome, GBS, GCA, GCM Syndrome, Binding Protein Deficiency, Growth Hormone Deficiency, GCPS, Gee-Herter Disease, Gee-Thaysen Disease, Gehrig's Growth-Mental Deficiency Syndrome of Myhre. Growth Disease, Gelineau's Syndrome, Genee-Wiedemann Syn Retardation-Rieger Anomaly, GRS. Gruber Syndrome, GS, drome, Generalized Dystonia, Generalized Familial Neu GSD6, GSD8, GTS, Guanosine Triphosphate-Cyclohydro romyotonia, Generalized Fibromatosis, Generalized Flexion lase Deficiency, Guanosine Triphosphate-Cyclohydrolase Epilepsy, Generalized Glycogenosis, Generalized Hyper Deficiency, Guenther Porphyria, Guerin-Stern Syndrome, US 2007/0021589 A1 Jan. 25, 2007 27

Guillain-Barré, Guillain-Barre Syndrome, Gunther Disease, Hereditary Nephritis, Hereditary Nephritis and Nerve Deaf H Disease, H. Gottron’s Syndrome, Habit Spasms, HAE, ness, Hereditary Nephropathic Amyloidosis, Hereditary Hageman Factor Deficiency, Hageman factor, Haim-Munk Nephropathy and Deafness, Hereditary Nonpolyposis Col Syndrome, Hajdu-Cheney Syndrome, Hajdu Cheney, HAL orectal Cancer, Hereditary Nonpolyposis Colorectal Carci Deficiency, Hall-Pallister Syndrome, Hallermann-Streiff noma, Hereditary Nonspherocytic Hemolytic Anemia, Francois syndrome, Hallermann-Streiff Syndrome, Haller Hereditary Onychoosteodysplasia, Hereditary Optic Neu Vorden-Spatz Disease, Hallervorden-Spatz Syndrome, Hal roretinopathy, Hereditary Polyposis Coli, Hereditary Sen lopeau-Siemens Disease, Hallux Duplication Postaxial sory and Autonomic Neuropathy Type I, Hereditary Sensory Polydactyly and Absence of Corpus Callosum, Halushi and Autonomic Neuropathy Type II, Hereditary Sensory and Behcet’s Syndrome, Hamartoma of the Lymphatics, Hand Autonomic Neuropathy Type III, Hereditary Sensory Motor Schueller-Christian Syndrome, HANE, Hanhart Syndrome, Neuropathy, Hereditary Sensory Neuropathy type I, Heredi Happy Puppet Syndrome, Harada Syndrome, HARD +E tary Sensory Neuropathy Type I, Hereditary Sensory Neu Syndrome, HARD Syndrome, Hare Lip, Harlequin Fetus, ropathy Type II, Hereditary Sensory Neuropathy Type III, Harlequin Type DOC 6, Harlequin Type Ichthyosis, Harley Hereditary Sensory Radicular Neuropathy Type I, Heredi Syndrome, Harrington Syndrome, Hart Syndrome, Hartnup tary Sensory Radicular Neuropathy Type I, Hereditary Sen Disease, Hartnup Disorder, Hartnup Syndrome, Hashimo sory Radicular Neuropathy Type II, Hereditary Site Specific to's Disease, Hashimoto-Pritzker Syndrome, Hashimoto's Cancer. Hereditary Spherocytic Hemolytic Anemia, Heredi Syndrome, Hashimoto's Thyroiditis, Hashimoto-Pritzker tary Spherocytosis, Hereditary Type 1, Heri Syndrome, Hay Wells Syndrome, Hay-Wells Syndrome of table Connective Tissue Disorders, Herlitz Syndrome, Her Ectodermal Dysplasia, HCMM, HCP, HCTD, HD, Heart mans-Herzberg Phakomatosis, Hermansky-Pudlak Hand Syndrome (Holt-Oram Type), Heart Disease, Hecht Syndrome, Hermaphroditism, Herpes Zoster, Herpes Iris Syndrome, HED, Heerferdt-Waldenstrom and Lofgren's Stevens-Johnson Type, Hers Disease, Heterozygous Beta Syndromes, Hegglin's Disease, Heinrichsbauer Syndrome, Thalassemia, Hexoaminidase Alpha-Subunit Deficiency Hemangiomas, Hemangioma Familial, Hemangioma (Variant B), Hexoaminidase Alpha-Subunit Deficiency Thrombocytopenia Syndrome, Hemangiomatosis Chondro (Variant B), HFA, HFM, HOPS, HH, HHHO, HHRH, HHT, dystrophica, Hemangiomatous Branchial Clefts-Lip Hiatal Hernia-Microcephaly-Nephrosis Galloway Type, Pseudocleft Syndrome, Hemifacial Microsomia, Hidradenitis Suppurativa, Hidrosadenitis Axillaris, Hidro Hemimegalencephaly, Hemiparesis of Cerebral Palsy, sadenitis Suppurativa, Hidrotic Ectodermal Dysplasias, HIE Hemiplegia of Cerebral Palsy, Hemisection of the Spinal Syndrome, High Imperforate Anus, High Potassium, High Cord, Hemochromatosis, Hemochromatosis Syndrome, Scapula, HIM, Hirschsprung's Disease, Hirschsprung's Dis Hemodialysis-Related Amyloidosis, Hemoglobin Lepore ease Acquired, Hirschsprung Disease Polydactyly of Ulnar Syndromes, Hemolytic Anemia of Newborn, Hemolytic & Big Toe and VSD, Hirschsprung Disease with Type D Cold Antibody Anemia, Hemolytic Disease of Newborn, Brachydactyly, Hirsutism, HIS Deficiency. Histidine Hemolytic-Uremic Syndrome, Hemophilia, Hemophilia A, Ammonia-Lyase (HAL) Deficiency. Histidase Deficiency, Hemophilia B, Hemophilia B Factor IX, Hemophilia C, , Histiocytosis. Histiocytosis X, HLHS, HLP Hemorrhagic Dystrophic Thrombocytopenia, Hemorrhagica Type II, HMG, HMI, HMSN I, HNHA, HOCM, Hodgkin Aleukia, Hemosiderosis, Hepatic Fructokinase Deficiency, Disease, Hodgkin’s Disease, Hodgkin’s Lymphoma, Hol Hepatic Phosphorylase Kinase Deficiency, Hepatic Porphy laender-Simons Disease, Holmes-Adie Syndrome, Holocar ria, Hepatic Porphyrias, Hepatic Veno-Occlusive Diseas, boxylase Synthetase Deficiency, Holoprosencephaly, Holo Hepato-Renal Syndrome, Hepatolenticular Degeneration, prosencephaly Malformation Complex, Holoprosencephaly Hepatophosphorylase Deficiency, Hepatorenal Glycogeno Sequence, Holt-Oram Syndrome, Holt-Oram Type Heart sis, Hepatorenal Syndrome, Hepatorenal Tyrosinemia, Hand Syndrome, Homocystinemia, , Hereditary Acromelalgia, Hereditary Alkaptonuria, Heredi Oxidase Deficiency, Homogentisic Aci tary Amyloidosis, Hereditary Angioedema, Hereditary dura, Homozygous Alpha-1-Antitrypsin Deficiency, HOOD, Areflexic Dystasia, Heredopathia Atactica Polyneuritifor Homer Syndrome, Horton's disease, HOS, HOS1, Houston mis, Hereditary Ataxia, Hereditary Ataxia Friedrich's Type, Harris Type Achrondrogenesis (Type IA), HPS, HRS, HS, Hereditary Benign Acanthosis Nigricans, Hereditary Cer HSAN Type I, HSAN Type II, HSAN-III, HSMN, HSMN ebellar Ataxia, Hereditary Chorea, Hereditary Chronic Pro Type III, HSN I, HSN-III, Huebner-Herter Disease, Hun gressive Chorea, Hereditary Connective Tissue Disorders, ner's Patch, Hunner's Ulcer, Hunter Syndrome, Hunter Hereditary Coproporphyria, Hereditary Coproporphyria Thompson Type Acromesomelic Dysplasia, Huntington's Porphyria, Hereditary Cutaneous Malignant Melanoma, Chorea, Huntington's Disease, Hurler Disease, Hurler Syn Hereditary Deafness-Retinitis Pigmentosa, Heritable Disor drome, Hurler-Scheie Syndrome, HUS, Hutchinson-Gilford der of Zinc Deficiency, Hereditary DNS, Hereditary Dys Progeria Syndrome, Hutchinson-Cilford Syndrome, Hutch topic Lipidosis, Hereditary Emphysema, Hereditary Fruc inson-Weber-Peutz Syndrome, Hutterite Syndrome Bowen tose Intolerance, Hereditary Hemorrhagic Telangiectasia, Conradi Type, Hyaline Panneuropathy, Hydranencephaly, Hereditary Hemorrhagic Telangiectasia Type I, Hereditary Hydrocephalus, Hydrocephalus Agyria and Retinal Dyspla Hemorrhagic Telangiectasia Type H, Hereditary Hemor sia, Hydrocephalus Internal Dandy-Walker Type, Hydro rhagic Telangiectasia Type III. Hereditary Hyperuricemia cephalus Noncommunicating Dandy-Walker Type, Hydro and Choreoathetosis Syndrome, Hereditary Leptocytosis cephaly, Hydronephrosis With Peculiar Facial Expression, Major, Hereditary Leptocytosis Minor, Hereditary Lymphe Hydroxylase Deficiency, Hygroma Colli, Hyper-IgE Syn dema, Hereditary Lymphedema Tarda, Hereditary Lymphe drome, Hyper-IgM Syndrome, Hyperaldosteronism, Hyper dema Type I, Hereditary Lymphedema Type II, Hereditary aldosteronism With Hypokalemic Alkatosis, Hyperaldoster Motor Sensory Neuropathy, Hereditary Motor Sensory Neu onism Without Hypertension, , ropathy I, Hereditary Motor Sensory Neuropathy Type III, Hyperammonemia Due to Carbamylphosphate Synthetase US 2007/0021589 A1 Jan. 25, 2007 28

Deficiency, Hyperammonemia Due to Ornithine Transcar Ichthyosiform Erythroderma Corneal Involvement and bamylase Deficiency, Hyperammonemia Type II, Hyper Deafness, Ichthyosiform Erythroderma Hair Abnormality Beta Carnosinemia, Hyperbilirubinemia I, Hyperbilirubine Growth and Men, Ichthyosiform Erythroderma with Leuko mia II, Hypercalcemia Familial with Nephrocalcinosis and cyte Vacuolation, Ichthyosis, Ichthyosis Congenita, Ichthyo Indicanuria, Hypercalcemia-Supravalvar Aortic Stenosis, sis Congenital with Trichothiodystrophy, Ichthyosis Hystrix, Hypercalciuric Rickets, Hypercapnic acidosis, Hypercata Ichthyosis Hystrix Gravior, Ichthyosis Linearis Circum bolic Protein-Losing Enteropathy, Hyperchloremic acidosis, flexa, Ichthyosis Simplex, Ichthyosis Tay Syndrome, Ich Hypercholesterolemia, Hypercholesterolemia Type IV. thyosis Vulgaris, Ichthyotic Neutral Lipid Storage Disease, Hyperchylomicronemia, Hypercystinuria, Hyperekplexia, Icteric Leptospirosis, Icterohemorrhagic Leptospirosis, Ict Hyperextensible joints, Hyperglobulinemic Purpura, Hyper erus (Chronic Familial), Icterns Gravis Neonatorum, Icterus glycinemia with Ketoacidosis and Lactic Acidosis Propionic Intermittens Juvenalis, Idiopathic Alveolar HypoVentilation, Type, Hyperglycinemia Nonketotic, Hypergonadotropic Idiopathic Amyloidosis, Idiopathic Arteritis of Takayasu, Hypogonadism, Hyperimmunoglobulin E Syndrome, Idiopathic Basal Ganglia Calcification (I13GC), Idiopathic Hyperimmunoglobulin E-Recurrent Infection Syndrome, Brachial Plexus Neuropathy, Idiopathic Cervical Dystonia, Hyperimmunoglobulinemia E-Staphylococcal, Hyperkale Idiopathic Dilatation of the Pulmonary Artery, Idiopathic mia, Hyperkinetic Syndrome, Hyperlipemic Retinitis, Facial Palsy, Idiopathic Familial Hyperlipemia, Idiopathic Hyperlipidemia I, Hyperlipidemia IV. Hyperlipoproteinemia Hypertrophic Subaortic Stenosis, Idiopathic Hypoproteine Type I, Hyperlipoproteinemia Type III, Hyperlipoproteine mia, Idiopathic Immunoglobulin Deficiency, Idiopathic mia Type IV. Hyperoxaluria, Hyperphalangy-Clinodactyly Neonatal Hepatitis, Idiopathic Non-Specific Ulcerative of Index Finger with Pierre Robin Syndrome, Hyperpheny Colitis, Idiopathic Peripheral Periphlebitis, Idiopathic Pul lalanemia, Hyperplastic Epidermolysis Bullosa, Hyperpnea, monary Fibrosis, Idiopathic Refractory Sideroblastic Ane Hyperpotassemia, Hyperprebeta-Lipoproteinemia, Hyper mia, Idiopathic Renal Hematuria, Idiopathic Steatorrhea, prolinemia Type I, Type II, Hyper Idiopathic Thrombocythemia, Idiopathic Thrombocytopenic splenism, Hypertelorism with Esophageal Abnormalities Purpura, Idiopathic Thrombocytopenia Purpura (ITP), and Hypospadias, Hypertelorism-Hypospadias Syndrome, IDPA, IgA Nephropathy, IHSS, Ileitis, Ileocolitis, Illinois Hypertrophic Cardio myopathy, Hypertrophic Interstitial Type Amyloidosis, ILS, IM, IMD2, IMD5, Immune Defect Neuropathy, Hypertrophic Interstitial Neuritis, Hypertrophic due to Absence of Thymus, Immune Hemolytic Anemia Interstitial Radiculoneuropathy, Hypertrophic Neuropathy Paroxysmal Cold, Immunodeficiency with Ataxia Telang of Refsum, Hypertrophic Obstructive Cardio myopathy, iectasia, Immunodeficiency Cellular with Abnormal Immu Hyperuricemia Choreoathetosis Self-multilation Syndrome, noglobulin Synthesis, Immunodeficiency Common Variable Hyperuricemia-Oligophrenia, , Hypocalci Unclassifiable, Immunodeficiency with Hyper-IgM, Immu fied (Hypomineralized) Type, Hypochondrogenesis, Hypo nodeficiency with Leukopenia, Immunodeficiency-2, Immu chrondroplasia, Hypogammaglobulinemia, Hypogamma nodeficiency-5 (IMD5). Immunoglobulin Deficiency, globulinemia Transient of Infancy, Hypogenital Dystrophy Imperforate Anus, Imperforate Anus with Hand Foot and with Diabetic Tendency, Hypoglossia-Hypodactylia Syn Ear Anomalies, Imperforate Nasolacrimal Duct and Prema drome, Hypoglycemia, Exogenous Hypoglycemia, ture Aging Syndrome, Impotent Neutrophil Syndrome, Hypoglycemia with Macroglossia, Hypoglycosylation Syn Inability To Open Mouth Completely And Short Finger drome Type la, Hypoglycosylation Syndrome Type 1a, Flexor, INAD. Inborn Error of Urea Synthesis Arginase Hypogonadism with Anosmia, Hypogonadotropic Hypogo Type, Inborn Error of Urea Synthesis Arginino Succinic nadism and Anosmia, Hypohidrotic Ectodermal Dysplasia, Type, Inborn Errors of Urea Synthesis Carbamyl Phosphate Hypohidrotic Ectodermal Dysplasia Autosomal Dominant Type, Inborn Error of Urea Synthesis Citrullinemia Type, type, Hypohidrotic Ectodermal Dysplasias Autorecessive, Inborn Errors of Urea Synthesis Glutamate Synthetase Type, Hypokalemia, Hypokalemic Alkalosis with Hypercalciuria, INCL, Inclusion body myositis, Incomplete Atrioventricular Hypokalemic Syndrome, Hypolactasia, Hypomaturation Septal Defect, Incomplete Testicular Feminization, Inconti Type (Snow-Capped Teeth), Hypomelanosis of Ito, nentia Pigmenti, Incontinenti Pigmenti Achromians, Index Hypomelia-Hypotrichosis-Facial Hemangioma Syndrome, Finger Anomaly with Pierre Robin Syndrome, Indiana Type Hypomyelination Neuropathy, Hypoparathyroidism, Hypo Amyloidosis (Type II), Indolent systemic mastocytosis, phosphatasia, Hypophosphatemic Rickets with Hypercalce Infantile Acquired Aphasia, Infantile Autosomal Recessive mia, Hypopigmentation, Hypopigmented macular lesion, Polycystic Kidney Disease, Infantile Beriberi, Infantile Hypoplasia of the Depressor Anguli Oris Muscle with Cerebral Ganglioside, Infantile Cerebral Paralysis, Infantile Cardiac Defects, Hypoplastic Anemia, Hypoplastic Con Cystinosis, Infantile Epileptic, Infantile Fanconi Syndrome genital Anemia, Hypoplastic Chondrodystrophy, Hypoplas with Cystinosis, Infantile Finnish Type Neuronal Ceroid tic Enamel-Onycholysis-Hypohidrosis, Hypoplastic (Hypo Lipofuscinosis, Infantile Gaucher Disease, Infantile plastic-Explastic) Type, Hypoplastic Left Heart Syndrome, Hypoglycemia, Infantile Hypophasphatasia, Infantile Lobar Hypoplastic-Triphalangeal Thumbs, Hypopotassemia Syn Emphysema, Infantile Myoclonic Encephalopathy, Infantile drome, Hypospadias-Dysphagia Syndrome, Hyposmia, Myoclonic Encephalopathy and Polymyoclonia, Infantile Hypothalamic Hamartoblastoma Hypopituitarism Imperfo Myofibromatosis, Infantile Necrotizing Encephalopathy, rate Anus Polydactyly, Hypothalamic Infantilism-Obesity, Infantile Neuronal Ceroid Lipofuscinosis, Infantile Neu Hypothyroidism, Hypotonia-Hypomentia-Hypogonadism roaxonal Dystrophy, Infantile Onset Schindler Disease, Obesity Syndrome, Hypoxanthine-Guanine Phosphoribo Infantile Phytanic Acid Storage Disease, Infantile Refsum syltran?ferase Defect (Complete Absense of), I-Cell Disease, Disease (IRD), Infantile Sipoidosis GM-2 Gangliosideosis Iatrogenic Hypoglycemia, IBGC, IBIDS Syndrome, IBM, (Type S), Infantile Sleep Apnea, Infantile Spasms, Infantile IBS, IC, I-Cell Disease, ICD, ICFE Syndrome Cogan-Reese Spinal Muscular Atrophy (all types), Infantile Spinal Mus Type, Icelandic Type Amyloidosis (Type VI), I-Cell Disease, cular Atrophy ALS, Infantile Spinal Muscular Atrophy Type US 2007/0021589 A1 Jan. 25, 2007 29

I, Infantile Type Neuronal Ceroid Lipofuscinosis, Infectious Syndrome, KBG Syndrome, KD, Kearns-Sayre Disease, Jaundice, Inflammatory Breast Cancer, Inflammatory Linear Kearns-Sayre Syndrome, Kennedy Disease, Kennedy Syn Nevus Sebaceous Syndrome. Iniencephaly, Insulin Resistant drome, Kennedy Type Spinal and Bulbar Muscular Atrophy, Acanthgsis Nigricans, Insulin Lipodystrophy, Insulin depen Kennedy-Stefanis Disease, Kenny Disease, Kenny Syn dent Diabetes, Intention Myoclonus, Intermediate Cystino drome, Kenny Type Tubular Stenosis, Kenny-Caffe Syn sis, Intermediate Maple Syrup Urine Disease, Intermittent drome, Kera. Palmoplant. Con. Pes Planus Ony. Periodon. Ataxia with Pyruvate Dehydrogenase Deficiency, Intermit Arach. Keratitis Ichthyosis Deafness Syndrome, Keratoco tent Maple Syrup Urine Disease, Internal Hydrocephalus, nus, Keratoconus Posticus Circumscriptus, Keratolysis, Interstitial Cystitis, Interstitial Deletion of 4q Included, Keratolysis Exfoliativa Congenita, Keratolytic Winter Intestinal Lipodystrophy, Intestinal Lipophagic Granuloma Erythema, Keratomalacia, Keratosis Follicularis, Keratosis tosis, Intestinal Lymphangiectasia, Intestinal Polyposis I. Follicularis Spinulosa Decalvans, Keratosis Follicularis Intestinal Polyposis II, Intestinal Polyposis III, Intestinal Spinulosa Decalvans Ichthyosis, Keratosis Nigricans, Kera Polyposis-Cutaneous Pigmentation Syndrome, Intestinal tosis Palmoplantaris with Periodontopathia and Onychogry Pseudoobstruction with External Ophthalmoplegia, Intrac posis, Keratosis Palmoplantaris Congenital Pes Planus Ony ranial Neoplasm, Intracranial Tumors, Intracranial Vascular chogryposis Periodontosis Arachnodactyly, Keratosis Malformations, Intrauterine Dwarfism, Intrauterine Syn Palmoplantaris Congenital, Pes Planus, Onychogryphosis, echiae, Inverted Smile And Occult Neuropathic Bladder, Periodontosis, Arachnodactyly, Acroosteolysis, Keratosis Iowa Type Amyloidosis (Type IV), IP, IPA, Iridocorneal Rubra Figurata, Keratosis Seborrheica, Ketoacid Decar Endothelial Syndrome, Iridocorneal Endothelial (ICE) Syn boxylase Deficiency, Ketoaciduria, Ketotic Glycinemia, drome Cogan-Resse Type, Iridogoniodysgenesis With KFS, KID Syndrome, Kidney Agenesis, Kidneys Cysfic Somatic Anomalies, Iris Atrophy with Corneal Edema and Retinal Aplasia Joubert Syndrome, Killian Syndrome, Kil Glaucoma, Iris Nevus Syndrome, Iron Overload Anemia, lian/Teschler-Nicola Syndrome, Kiloh-Nevin syndrome III, Iron Overload Disease, Irritable Bowel Syndrome, Irritable Kinky Hair Disease, Kinsboume Syndrome, Kleeb Colon Syndrome, Isaacs Syndrome, Isaacs-Merten Syn lattschadel Deformity, Kleine-Levin Syndrome, Kleine drome, Ischemic Cardio myopathy, Isolated Lissencephaly Levin Hibernation Syndrome, Klinefelter, Klippel-Feil Syn Sequence, Isoleucine 33 Amyloidosis, Isovaleric Acid CoA drome, Klippel-Feil Syndrome Type I, Klippel-Feil Dehydrogenase Deficiency, Isovaleric Acidaemia, Isovaleri Syndrome Type II, Klippel-Feil Syndrome Type III, Klippel cacidemia, Isovaleryl CoA Carboxylase Deficiency, ITO Trenaunay Syndrome, Klippel-Trenaunay-Weber Syn Hypomelanosis, ITO, ITP, IVA, Ivemark Syndrome, Iwanoff drome, Kluver-Bucy Syndrome, KMS, Kniest Dysplasia, Cysts, Jackknife Convulsion, Jackson-Weiss Craniosynos Kniest Syndrome, Kobner's Disease, Koebberling-Dunni tosis, Jackson-Weiss Syndrome, Jacksonian Epilepsy, Jacob gan Syndrome, Kohlmeier-Degos Disease, Kok Disease, Sen Syndrome, Jadassohn-Lewandowsky Syndrome, Jaffe Korsakoff Psychosis, Korsakoff’s Syndrome, Krabbe's Dis Lichenstein Disease, Jakob's Disease, Jakob-Creutzfeldt ease Included, Krabbe's Leukodystrophy, Kramer Syn Disease, Janeway I, Janeway Dysgammaglobulinemia, Jan drome, KSS, KTS, KTW Syndrome, Kufs Disease, Kugel sen Metaphyseal Dysostosis, Jansen Type Metaphyseal berg-Welander Disease, Kugelberg-Welander Syndrome, Chondrodysplasia, Jarcho-Levin Syndrome, Jaw-Winking, Kussmaul-Landry Paralysis, KWS, L-3-Hydroxy-Acyl-CoA JBS, JDMS, Jegher's Syndrome, Jejunal Atresia, Jeunitis, Dehydrogenase (LCHAD) Deficiency, Laband Syndrome, Jejunoileitis, Jervell and Lange-Nielsen Syndrome, Jeune Labhart-Willi Syndrome, Labyrinthine Syndrome, Labyrin Syndrome, JMS, Job Syndrome, Job-Buckley Syndrome, thine Hydrops, Lacrimo-Auriculo-Dento-Digital Syndrome, Johanson-Blizzard Syndrome, John Dalton, Johnson Lactase Isolated Intolerance, Lactase Deficiency, Lactation Stevens Disease, Jonston's Alopecia, Joseph’s Disease, Uterus Atrophy, Lactic Acidosis Leber Hereditary Optic Joseph’s Disease Type I, Joseph's Disease Type II, Joseph's Neuropathy, Lactic and Pyruvate Acidemia with Carbohy Disease Type III, Joubert Syndrome, Joubert-Bolthauser drate Sensitivity, Lactic and Pyruvate Acidemia with Epi Syndrome, JRA, Juberg Hayward Syndrome, Juberg-Mar sodic Ataxia and Weakness, Lactic and Pyruvate, Lactic sidi Syndrome, Juberg-Marsidi Mental Retardation Syn acidosis, Lactose Intolerance of Adulthood, Lactose Intol drome, Jumping Frenchmen, Jumping Frenchmen of Maine, erance, Lactose Intolerance of Childhood, LADD Syn Juvenile Arthritis, Juvenile Autosomal Recessive Polycystic drome, LADD, Lafora Disease Included, Lafora Body Dis Kidney Disease, Juvenile Cystinosis, Juvenile (Childhood) ease, Laki-Lorand Factor Deficiency, LAM, Lambert Type Dermatomyositis (JDMS), Juvenile Diabetes, Juvenile Gau Ichthyosis, Lambert-Eaton Syndrome, Lambert-Eaton cher Disease, Juvenile Gout Choreoathetosis and Mental Myasthenic Syndrome, Lamellar Recessive Ichthyosis, Retardation Syndrome, Juvenile Intestinal Malabsorption of Lamellar Ichthyosis, Lancereaux-Mathieu-Weil Spirocheto Vit B12, Juvenile Intestinal Malabsorption of Vitamin B12, sis, Landau-Kleffner Syndrome, Landouzy Dejerine Mus Juvenile Macular Degeneration, Juvenile Pernicious Ane cular Dystrophy, Landry Ascending Paralysis, Langer-Sali mia, Juvenile Retinoschisis, Juvenile Rheumatoid Arthritis, dino Type Achondrogensis (Type II), Langer Giedion Juvenile Spinal Muscular Atrophy Included, Juvenile Spinal Syndrome, Langerhans-Cell Granulomatosis, Langerhans Muscular Atrophy AILS Included, Juvenile Spinal Muscular Cell Histiocytosis (LCH), Large Atrial and Ventricular Atrophy Type III, Juxta-Articular Adiposis Dolorosa, Juxta Defect, Laron Dwarfism, Laron Type Pituitary Dwarfism, glomerular Hyperplasia, Kabuki Make-Up Syndrome, Larsen Syndrome, Laryngeal Dystonia, Latah (Observed in Kahler Disease, Kallmann Syndrome, Kanner Syndrome, Malaysia), Late Infantile Neuroaxonal Dystrophy, Late Kanzaki Disease, Kaposi Disease (not Kaposi Sarcoma), Infantile Neuroaxonal Dystrophy, Late Onset Cockayne Kappa Light Chain Deficiency, Karsch-Neugebauer Syn Syndrome Type III (Type C), Late-Onset Dystonia, Late drome, Kartagener Syndrome-Chronic Sinobronchial Dis Onset linmunoglobulin Deficiency, Late Onset Pelizaeus ease and Dextrocardia, Kartagener Triad, Kasabach-Merritt Merzbacher Brain Sclerosis, Lattice Corneal Dystrophy, Syndrome, Kast Syndrome, Kawasaki Disease, Kawasaki Lattice Dystrophy, Launois-Bensaude, Launois-Cleret Syn US 2007/0021589 A1 Jan. 25, 2007 30 drome, Laurence Syndrome, Laurence-Moon Syndrome, Lowe-Terry-MacLachlan Syndrome, LS, LTD), Lubs Syn Laurence-Moon/Bardet-Biedl, Lawrence-Seip Syndrome, drome, Luft Disease, Lumbar Canal Stenosis, Lumbar Spi LCA, LCAD Deficiency, LCAD, LCAD, LCADH Defi nal Stenosis, Lumbosacral Spinal Stenosis, Lundborg-Un ciency, LCH. LCHAD, LCPD, LeJeune Syndrome, Leband verricht Disease, Lundborg-Unverricht Disease Included, Syndrome, Leber's Amaurosis, Leber's Congenital Amau Lupus, Lupus, Lupus Erythematosus, Luschka-Magendie rosis, Congenital Absence of the Rods and Cones, Leber's Foramina Atresia, Lyell Syndrome, Lyelles Syndrome, Lym Congenital Tapetoretinal Degeneration, Leber's Congenital phadenoid Goiter, Lymphangiectatic Protein-Losing Enter Tapetoretinal Dysplasia, Leber's Disease, Leber's Optic opathy, Lymphangioleiomatosis, Lymphangioleimyomato Atrophy, Leber's Optic Neuropathy, Left Ventricular Fibro sis, Lymphangiomas, Lymphatic Malformations, Lynch sis, Leg Ulcer, Legg-Calve-Perthes Disease, Leigh's Dis Syndromes, Lynch Syndrome I, Lynch Syndrome II, Lyso ease, Leigh's Syndrome, Leigh's Syndrome (Subacute Somal Alpha-N-Acetylgalactosaminidase Deficiency Schin Necrotizing Encephalomyelopathy), Leigh Necrotizing dler Type, Lysosomal Glycoaminoacid Storage Disease Encephalopathy, Lennox-Gastaut Syndrome, Lentigio-Poly Angiokeratoma Corporis Diffusum, Lysosomal Glucosidase pose-Digestive Syndrome, Lenz, Dysmorphogenetic Syn Deficiency, MAA, Machado Disease, Machado-Joseph Dis drome, Lenz, Dysplasia, Lenz, Microphthalmia Syndrome, ease, Macrencephaly, Macrocephaly, Macrocephaly Hemi Lenz, Syndrome, LEOPARD Syndrome, Leprechaunism, hypertrophy, Macrocephaly with Multiple Lipomas and Leptomeningeal Angiomatosis, Leptospiral Jaundice, Leri Hemangiomata, Macrocephaly with Pseudopapilledema and Weill Disease, Leri-Weil Dyschondrosteosis, Leri-Weil Syn Multiple Hemangiomata, Macroglobulinemia, Macroglos drome, LermoyeZ Syndrome, Leroy Disease, Lesch Nyhan sia, Macroglossia-Omphalocele-Visceromegaly Syndrome, Syndrome, Lethal Infantile Cardio myopathy, Lethal Neo Macrostomia Ablepheron Syndrome, Macrothrombocytope natal Dwarfism, Lethal Osteochondrodysplasia, Letterer nia Familial Bernard-Soulier Type, Macula Lutea degenera Siwe Disease, Leukocytic Anomaly Albinism, Leukocytic tion, Macular Amyloidosis, Macular Degeneration, Macular Inclusions with Platelet Abnormality, Leukodystrophy, Leu Degeneration Disciform, Macular Degeneration Senile, kodystrophy with Rosenthal Fibers, Leukoencephalitis Peri Macular Dystrophy, Macular Type Corneal Dystrophy, axialis Concentric, Levine-Critchley Syndrome, Levulo MAD, Madelung’s Disease, Maffucci Syndrome, Major suria, Levy-Hollister Syndrome, LGMD, LGS, LHON, LIC, Epilepsy, Malabsorption, Malabsorption-Ectodermal Dys Lichen Ruber Acuminatus, Lichen Acuminatus, Lichen plasia-Nasal Alar Hypoplasia, Maladie de Roger, Maladie de Amyloidosis, Lichen Planus, Lichen Psoriasis, Lignac-De Tics, Male Malformation of Limbs and Kidneys, Male bre-Fanconi Syndrome, Lignac-Fanconi Syndrome, Ligne Turner Syndrome, Malignant Acanthosis, Malignant Acan ous Conjunctivitis, Limb-Girdle Muscular Dystrophy, Limb thosis Nigricans, Malignant Astrocytoma, Malignant Atro Malformations-Dento-Digital Syndrome, Limit Dextrinosis, phic Papulosis, Malignant Fever, Malignant Hyperphenyla Linear Nevoid Hypermelanosis, Linear Nevus Sebacous laninemia, Malignant Hyperpyrexia, Malignant Syndrome, Linear Scleroderma, Linear Sebaceous Nevus Hyperthermia, Malignant Melanoma, Malignant Tumors of Sequence, Linear Sebaceous Nevus Syndrome, Lingua Fis the Central Nervous System, Mallory-Weiss Laceration, Surata, Lingua Plicata, Lingua Scrotalis, Linguofacial Dys Mallory-Weiss Tear, Mallory-Weiss Syndrome, Mammary kinesia, Lip Pseudocleft-hemangiomatous Branchial Cyst Paget’s Disease, Mandibular Ameloblastoma, Mandibulofa Syndrome, Lipid Granulomatosis, Lipid Histiocytosis, Lipid cial Dysostosis, Mannosidosis, Map-Dot-Fingerprint Type Kerasin Type, Lipid Storage Disease, Lipid-Storage myopa Corneal Dystrophy, Maple Syrup Urine Disease, Marble thy Associated with SCAD Deficiency, Lipidosis Ganglio Bones, Marchiafava-Micheli Syndrome, Marcus Gunn Jaw side Infantile, Lipoatrophic Diabetes Mellitus, Lipodystro Winking Syndrome, Marcus Gunn Phenomenon, Marcus phy, Lipoid Corneal Dystrophy, Lipoid Hyperplasia-Male Gunn Ptosis with jaw-winking, Marcus Gunn Syndrome, Pseudohermaphroditism, Lipomatosis of Pancreas Congeni Marcus Gunn (Jaw-Winking) Syndrome, Marcus (lunn Pto tal, Lipomucopolysaccharidosis Type I, Lipomyelomenin sis (with jaw-winking), Marden-Walker Syndrome, Marden gocele, Lipoprotein Lipase Deficiency Familial, LIS, LIS1, Walker Type Connective Tissue Disorder, Marfan's Abiotro Lissencephaly 1, Lissencephaly Type I, Lissencephaly vari phy, Marfan-Achard syndrome, Marfan Syndrome, ants with agenesis of the corpus callosum cerebellar hypo Marfan's Syndrome I, Marfans Variant, Marfanoid Hyper plasia or other anomalies, Little Disease, Liver Phosphory mobility Syndrome, Marginal Corneal Dystrophy, Maries lase Deficiency, LKS, LM Syndrome, Lobar Atrophy, Lobar Ataxia, Marie Disease, Marie-Sainton Disease, Marie Atrophy of the Brain, Lobar Holoprosencephaly, Lobar Strumpell Disease, Marie-Strumpell Spondylitis, Mari Tension Emphysema in Infancy, Lobstein Disease (Type I), nesco-Sjogren Syndrome, Marinesco-Sjogren-Gorland Syn Lobster Claw Deformity, Localized Epidermolysis Bullosa, drome, Marker X Syndrome, Maroteaux Lamy Syndrome, Localized Lipodystrophy, Localized Neuritis of the Shoul Maroteaux Type Acromesomelic Dysplasia, Marshall's der Girdle, Loeffler's Disease, Loeffler Endomyocardial Ectodermal Dysplasias With Ocular and Hearing Defects, Fibrosis with Eosinophilia, Loeffler Fibroplastic Parietal Marshall-Smith Syndrome, Marshall Syndrome, Marshall Endocarditis, Loken Syndrome, Loken-Senior Syndrome, Type Deafness-Myopia-Cataract-Saddle Nose, Martin-Al Long-Chain 3-hydroxyacyl-CoA Dehydrogenase bright Syndrome, Martin-Bell Syndrome, Martorell Syn (LCHAD), Long Chain Acyl CoA Dehydrogenase Defi drome, MASA Syndrome, Massive Myoclonia, Mast Cell ciency, Long-Chain Acyl-CoA Dehydrogenase (ACADL), Leukemia, Mastocytosis, Mastocytosis With an Associated Long-Chain Acyl-CoA Dehydrogenase Deficiency, Long Hematologic Disorder, Maumenee Corneal Dystrophy, QT Syndrome without Deafness, Lou Gehrig's Disease, Lou Maxillary Ameloblastoma, Maxillofacial Dysostosis, Max Gehrig's Disease Included, Louis-Bar Syndrome, Low illonasal Dysplasia, Maxillonasal Dysplasia Binder Type, Blood Sugar, Low-Density Beta Lipoprotein Deficiency, Maxillopalpebral Synkinesis, May-Hegglin Anomaly, Low Imperforate Anus, Low Potassium Syndrome, Lowe MCAD Deficiency, MCAD, McArdle Disease, McCune syndrome, Lowe's Syndrome, Lowe-Bickel Syndrome, Albright, MCD, McKusick Type Metaphyseal Chondrodys US 2007/0021589 A1 Jan. 25, 2007 plasia, MCR, MCTD, Meckel Syndrome, Meckel-Gruber Mobitz I, Mobitz II, Mobius Syndrome, Moebius Syndrome, Syndrome, Median Cleft Face Syndrome, Mediterranean Moersch-Woltmann Syndrome, Mohr Syndrome, Moni Anemia, Medium-Chain Acyl-CoA dehydrogenase lethrix, Monomodal Visual Amnesia, Mononeuritis Multi (ACADM), Medium Chain Acyl-CoA Dehydrogenase plex, Mononeuritis Peripheral, Mononeuropathy Peripheral, (MCAD) Deficiency, Medium-Chain Acyl-CoA Dehydroge Monosomy 3p2, Monosomy 9p Partial, Monosomy 11q. nase Deficiency, Medullary Cystic Disease, Medullary Partial, Monosomy 13q Partial, Monosomy 18q Syndrome, Sponge Kidney, MEF, Megaesophagus, Megalencephaly, Monosomy X, Monostotic Fibrous Dysplasia, Morgagni Megalencephaly with Hyaline Inclusion, Megalencephaly Turner-Albright Syndrome, Morphea, Morquio Disease, with Hyaline Panneuropathy, Megaloblastic Anemia, Mega Morquio Syndrome, Morquio Syndrome A. Morquio Syn loblastic Anemia of Pregnancy, Megalocornea-Mental drome B. Morquio-Brailsford Syndrome, Morvan Disease, Retardation Syndrome, Meier-Gorlin Syndrome, Meige's Mosaic Tetrasomy 9p, Motor Neuron Disease, Motor Neu Lymphedema, Meige's Syndrome, Melanodermic Leukod ron Syndrome, Motor Neurone Disease, Motoneuron Dis ystrophy, Melanoplakia-Intestinal Polyposis, Melanoplakia ease, Motoneurone Disease, Motor System Disease (Focal Intestinal Polyposis, MELAS Syndrome, MELAS, Melkers and Slow), Moya-moya Disease, Moyamoya Disease, MPS, son Syndrome, Melnick-Fraser Syndrome, Melnick-Needles MPS I, MPS I H, MPS 1 H/S Hurler/Scheie Syndrome, MPS Osteodysplasty, Melnick-Needles Syndrome, Membranous I S Scheie Syndrome, MPS II, MPS IIA, MPS IIB, MPS Lipodystrophy, Mendes Da Costa Syndrome, Meniere Dis II-AR Autosomal Recessive Hunter Syndrome, MPS II-XR, ease, Méniere's Disease, Meningeal Capillary Angiomato MPS II-XR Severe Autosomal Recessive, MPS III, MPS III sis, Menkes Disease, Menke's Syndrome I, Mental Retar A B C and D Sanfiloppo A, MPS IV, MPS IV A and B dation Aphasia Shuffling Gait Adducted Thumbs (MASA), Morquio A, MPS V. MPS VI, MPS VI Severe Intermediate Mental Retardation-Deafness-Skeletal Abnormalities Mild Maroteaux-Lamy, MPS VII, MPS VII Sly Syndrome, Coarse Face with Full Lips, Mental Retardation with Hypo MPS VIII, MPS Disorder, MPS Disorder I, MPS Disorder II, plastic 5th Fingernails and Toenails, Mental Retardation MPS Disorder III, MPS Disorder VI, MPS Disorder Type with Osteocartilaginous Abnormalities, Mental Retradation VII, MRS, MS, MSA, MSD, MSL, MSS, MSUD, MSUD, X-linked with Growth Delay-Deafness-Microgenitalism, MSUD Type Ib, MSUD Type II, Mucocutaneous Lymph Menzel Type OPCA, Mermaid Syndrome, MERRF, Node Syndrome, Mucolipidosis I, Mucolipidosis II, MERRF Syndrome, Merten-Singleton Syndrome, MES, Mucolipidosis III, Mucolipidosis IV. Mucopolysaccharido Mesangial IGA Nephropathy, Mesenteric Lipodystrophy, sis, Mucopolysaccharidosis I-H. Mucopolysaccharidosis Mesiodens-Cataract Syndrome, Mesodermal Dysmorphod I-S, Mucopolysaccharidosis II. Mucopolysaccharidosis III, ystrophy, Mesomelic Dwarfism-Madelung Deformity, Meta Mucopolysaccharidosis IV. Mucopolysaccharidosis VI, bolic Acidosis, Metachromatic Leukodystrophy, Metatarsus Mucopolysaccharidosis VII, Mucopolysaccharidosis Type I, Varus, Metatropic Dwarfism Syndrome, Metatropic Dyspla Mucopolysaccharidosis Type II. Mucopolysaccharidosis sia, Metatropic Dysplasia I, Metatropic Dysplasia II, Meth Type III, Mucopolysaccharidosis Type VII, Mucosis, Muco ylmalonic Acidemia, Methylmalonic Aciduria, Meulen sulfatidosis, Mucous Colitis, Mucoviscidosis, Mulibrey gracht’s Disease, MFD1, MG, MH, MHA, Micrencephaly, Dwarfism, Mulibrey Nanism Syndrome, Mullerian Duct Microcephalic Primordial Dwarfism I, Microcephaly, Aplasia-Renal Aplasia-Cervicothoracic Somite Dysplasia, Microcephaly-Hiatal Hernia-Nephrosis Galloway Type, Mullerian Duct-Renal-Cervicothoracic-Upper Limb Microcephaly-Hiatal Hernia-Nephrotic Syndrome, Micro Defects, Mullerian Duct and Renal Agenesis with Upper cystic Corneal Dystrophy, Microcythemia, Microlissen Limb and Rib Anomalies, Mullerian-Renal-Cervicothoracic cephaly, Microphthalmia, Microphthalmia or Anophthalmos Somite Abnormalities, Multi-Infarct Dementia with Associated Anomalies, Micropolygyria With Muscular Binswanger's Type, Multicentric Castleman's Disease, Mul Dystrophy, Microtia Absent Patellae Micrognathia Syn tifocal Eosinophilic Granuloma, Multiple Acyl-CoA Dehy drome, Microvillus Inclusion Disease, MID, Midsystolic drogenase Deficiency, Multiple Acyl-CoA Dehydrogenase click-late systolic murmur syndrome, Miescher's Type I Deficiency/Glutaric Aciduria Type II, Multiple Angiomas Syndrome, Mikulicz. Syndrome, Mikulicz-Radecki Syn and Endochondromas, Multiple Carboxylase Deficiency, drome, Mikulicz-Sjogren Syndrome, Mild Autosomal Multiple Cartilaginous Enchondroses, Multiple Cartilagi Recessive, Mild Intermediate Maple Syrup Urine Disease, nous Exostoses, Multiple Enchondromatosis, Multiple Mild Maple Syrup Urine Disease, Miller Syndrome, Miller Endocrine Deficiency Syndrome Type II, Multiple Epiphy Dieker Syndrome, Miller-Fisher Syndrome, Milfroy Disease, seal Dysplasia, Multiple Exostoses, Multiple Exostoses Syn Minkowski-Chauffard Syndrome, Minor Epilepsy, Minot drome, Multiple Familial Polyposis, Multiple Lentigines Von Willebrand Disease, Mirror-Image Dextrocardia, Mito Syndrome, Multiple Myeloma, Multiple Neuritis of the chondrial Beta-Oxidation Disorders, Mitrochondrial and Shoulder Girdle, Multiple Osteochondromatosis, Multiple Cytosolic, Mitochondrial Cytopathy, Mitochondrial Cytopa Peripheral Neuritis, Multiple Polyposis of the Colon, Mul thy, Kearn-Sayre Type, Mitochondrial Encephalopathy, tiple Pterygium Syndrome, Multiple Sclerosis, Multiple Mitochondrial Encephalo myopathy Lactic Acidosis and Sulfatase Deficiency, Multiple Symmetric Lipomatosis, Strokelike Episodes, Mitochondrial myopathy, Mitochon Multiple System Atrophy, Multisynostotic Osteodysgenesis, drial myopathy Encephalopathy Lactic Acidosis Stroke-Like Multisynostotic Osteodysgenesis with Long Bone Fractures, Episode, Mitochondrial PEPCK Deficiency, Mitral-valve Mulvihill-Smith Syndrome, MURCS Association, Murk prolapse, Mixed Apnea, Mixed Connective Tissue Disease, Jansen Type Metaphyseal Chondrodysplasia, Muscle Car Mixed Hepatic Porphyria, Mixed Non-Fluent Aphasia, nitine Deficiency, Muscle Core Disease, Muscle Phosphof Mixed Sleep Apnea, Mixed Tonic and Clonic Torticollis, ructokinase Deficiency, Muscular Central Core Disease, MJD, MKS, MLI, ML II, ML III, MLIV, ML Disorder Type Muscular Dystrophy, Muscular Dystrophy Classic X-linked I, ML Disorder Type II, ML Disorder Type III, ML Disorder Recessive, Muscular Dystrophy Congenital With Central Type IV, MLNS, MMR Syndrome, MND, MNGIE, MNS, Nervous System Involvement, Muscular Dystrophy Con US 2007/0021589 A1 Jan. 25, 2007 32 genital Progressive with Mental Retardation, Muscular Dys gic Amyotrophy, Neuraminidase Deficiency, Neuraocutane trophy Facioscapulohumeral, Muscular Rheumatism, Mus ous melanosis, Neurinoma of the Acoustic Nerve, cular Rigidity Progressive Spasm, Musculoskeletal Pain Neurinoma, Neuroacanthocytosis, Neuroaxonal Dystrophy Syndrome, Mutilating Acropathy, Mutism, mvp, MVP, Schindler Type, Neurodegeneration with brain iron accumu MWS, Myasthenia Gravis, Myasthenia Gravis Pseudopara lation type 1 (NBIA1), Neurofibroma of the Acoustic Nerve, lytica, Myasthenic Syndrome of Lambert-Eaton, Myelin Neurogenic Arthrogryposis Multiplex Congenita, Neuromy oclastic Diffuse Sclerosis, Myelomatosis, Myhre Syndrome, elitis Optica, Neuromyotonia, Neuromyotonia, Focal, Neu Myoclonic Astatic Petit Mal Epilepsy, Myoclonic Dystonia, romyotonia, Generalized, Familial, Neuromyotonia, Gener Myoclonic Encephalopathy of Infants, Myoclonic Epilepsy, alized, Sporadic, Neuronal Axonal Dystrophy Schindler Myoclonic Epilepsy Hartung Type, Myoclonus Epilepsy Type, Neuronal Ceroid Lipofuscinosis Adult Type, Neuronal Associated with Ragged Red Fibers, Myoclonic Epilepsy Ceroid Lipofuscinosis Juvenile Type, Neuronal Ceroid and Ragged-Red Fiber Disease, Myoclonic Progressive Lipofuscinosis Type 1, Neuronopathic Acute Gaucher Dis Familial Epilepsy, Myoclonic Progressive Familial Epi ease, Neuropathic Amyloidosis, Neuropathic Beriberi, Neu lepsy, Myoclonic Seizure, Myoclonus, Myoclonus Epilepsy, ropathy Ataxia and Retinitis Pigmentosa, Neuropathy of Myoencephalopathy Ragged-Red Fiber Disease, Myofibro Brachialpelxus Syndrome, Neuropathy Hereditary Sensory matosis, Myofibromatosis Congenital, Myogenic Facio Type I, Neuropathy Hereditary Sensory Type II, Neutral Scapulo-Peroneal Syndrome, Myoneurogastointestinal Dis Lipid Storage Disease, Nevii. Nevoid Basal Cell Carcinoma order and Encephalopathy, Myopathic Arthrogryposis Syndrome, Nevus, Nevus Cavernosus, Nevus Comedonicus, Multiplex Congenita, Myopathic Camitine Deficiency, Nevus Depigmentosus, Nevus Sebaceous of Jadassohn, Myopathy Central Fibrillar, myopathy Congenital Nonpro Nezelof's Syndrome, Nezelofs Thymic Aplasia, Nezelof gressive, myopathy Congenital Nonprogressive with Central Type Severe Combined Immunodeficiency, NF, NF1, NF2, Axis, myopathy with Deficiency of Carnitine Palmitoyl NF-1, NF-2, NHS, Niemann Pick Disease, Nieman Pick transferase, myopathy-Marinesco-Sjogren Syndrome, disease Type A (acute neuronopathic form), Nieman Pick myopathy-Metabolic Carnitine Palmitoyltransderase Defi disease Type B, Nieman Pick Disease Type C (chronic ciency, myopathy Mitochondrial-Encephalopathy-Lactic neuronopathic form), Nieman Pick disease Type D (Nova Acidosis-Stroke, myopathy with Sarcoplasmic Bodies and Scotia variant), Nieman Pick disease Type E, Nieman Pick Intermediate Filaments, Myophosphorylase Deficiency, disease Type F (sea-blue histiocyte disease), Night Blind Myositis Ossificans Progressiv, Myotonia Atrophica, Myo ness, Nigrospinodentatal Degeneration, Niikawakuroki Syn tonia Congenita, Myotonia Congenita Intermittens, Myo drome, NLS, NM, Noack Syndrome Type I, Nocturnal tonic Dystrophy, Myotonic myopathy Dwarfism Chondrod Myoclonus Hereditary Essential Myoclonus, Nodular Cor ystrophy Ocular and Facial Anomalies, Myotubular nea Degeneration, Non-Bullous CIE, Non-Bullous Congeni myopathy, Myotubular myopathy X-linked, Myproic Acid, tal Ichthyosiform Erythroderma, Non-Communicating Myriachit (Observed in Siberia), Myxedema, N-Acetylglu Hydrocephalus, Non-Deletion Type Alpha-Thalassemia/ cosamine-1-Phosphotransferase Deficiency, N-Acetyl Mental Retardation syndrome. Non-Ketonic Hyperglycin Glutamate Synthetase Deficiency, NADH-CoQ reductase emia Type I (NKHI), Non-Ketotic Hyperglycinemia, Non deficiency, Naegeli Ectodermal Dysplasias, Nager Syn Lipid Reticuloendotheliosis, Non-Neuronopathic Chronic drome, Nager Acrofacial Dysostosis Syndrome, Nager Syn Adult Gaucher Disease, Non-Scarring Epidermolysis drome, NAGS Deficiency, Nail Dystrophy-Deafness Syn Bullosa, Nonarteriosclerotic Cerebral Calcifications, Nonar drome, Nail Dysgenesis and Hypodontia, Nail-Patella ticular Rheumatism, Noncerebral, Juvenile Gaucher Dis Syndrome, Nance-Horan Syndrome, Nanocephalic Dwarf ease. Nondiabetic Glycosuria, Nonischemic Cardiomyopa ism, Nanocephaly, Nanophthalmia, Narcolepsy, Narcoleptic thy, Nonketotic Hypoglycemia and Carnitine Deficiency due syndrome, NARP, Nasal-fronto-faciodysplasia, Nasal Alar to MCAD Deficiency, Nonketotic Hypoglycemia Caused by Hypoplasia Hypothyroidism Pancreatic Achylia Congenital Deficiency of Acyl-CoA Dehydrogenase, Nonketotic Gly Deafness, Nasomaxillary Hypoplasia, Nasu Lipodystrophy, cinemia, Nonne’s Syndrome. Nonne-Milroy-Meige Syn NBIA1, ND, NDI, NDP. Necrotizing Encephalomyelopathy drome. Nonopalescent Opalescent Dentine. Nonpuerperal of Leigh's, Necrotizing Respiratory Ciranulomatosis, Neill Galactorrhea-Amenorrhea, Nonsecretory Myeloma, Non Dingwall Syndrome, Nelson Syndrome, Nemaline myopa spherocytic Hemolytic Anemia, Nontropical Sprue, Noonan thy, Neonatal Adrenoleukodystrophy, Neonatal Adrenoleu Syndrome, , Normal Pressure Hydroceph kodystrophy (NALD), Neonatal Adrenoleukodystrophy alus, Norman-Roberts Syndrome, Norrbottriian Gaucher (ALD), Neonatal Autosomal Recessive Polycystic Kidney Disease, Norrie Disease, Norwegian Type Hereditary Disease, Neonatal Dwarfism, Neonatal Hepatitis, Neonatal Cholestasis, NPD, NPS, NS, NSA, Nuchal Dystonia Hypoglycemia, Neonatal Lactose Intolerance, Neonatal Dementia Syndrome, Nutritional Neuropathy, Nyhan Syn Lymphedema due to Exudative Enteropathy, Neonatal Prog drome, OAV Spectrum, Obstructive Apnea, Obstructive eroid Syndrome, Neonatal Pseudo-Hydrocephalic Progeroid Hydrocephalus, Obstructive Sleep Apnea, OCC Syndrome, Syndrome of Wiedemann-Rautenstrauch, Neoplastic Arach Occlusive Thromboaortopathy, OCCS, Occult Intracranial noiditis, Nephroblastom, Nephrogenic Diabetes Insipidus, Vascular Malformations, Occult Spinal Dysraphism Nephronophthesis Familial Juvenile, Nephropathic Cystino Sequence, Ochoa Syndrome, Ochronosis, Ochronotic sis, Nephropathy-Pseudohermaphroditism-Wilms Tumor, Arthritis, OCR, OCRL, Octocephaly, Ocular Albinism, Ocu Nephrosis-Microcephaly Syndrome, Nephrosis-Neuronal lar Herpes, Ocular Myasthenia Gravis, Oculo-Auriculo Dysmigration Syndrome, Nephrotic-Glycosuric-Dwarfism Vertebral Dysplasia, Oculo-Auriculo-Vertebral Spectrum, Rickets-Hypophosphatemic Syndrome, Netherton Disease, Oculo-Bucco-Genital Syndrome, Oculocerebral Syndrome Netherton Syndrome, Netherton Syndrome Ichthyosis, with Hypopigmentation, Oculocerebrocutaneous. Syn Nettleship Falls Syndrome (X-Linked), Neu-Laxova Syn drome, Oculo-Cerebro-Renal, Oculocerebrorenal Dystro drome, Neuhauser Syndrome, Neural-tube defects, Neural phy, Oculocerebrorenal Syndrome, Oculocraniosomatic US 2007/0021589 A1 Jan. 25, 2007

Syndrome (obsolete), , Oculocu tal-Digital Syndrome Type II, Otodental Dysplasia, Otopala taneous Albinism Chediak-Higashi Type, Oculo-Dento todigital Syndrome, Otopalataldigital Syndrome Type II, Digital Dysplasia, Oculodentodigital Syndrome, Oculo Oudtshoorn Skin, Ovarian Dwarfism Turner Type, Ovary Dento-Osseous Dysplasia, Oculo Gastrointestinal Muscular Aplasia Turner Type, OWR, Oxalosis, Oxidase deficiency, Dystrophy, Oculo Gastrointestinal Muscular Dystrophy, Oxycephaly, Oxycephaly-Acrocephaly, P-V, PA, PAC, Oculomandibulodyscephaly with hypotrichosis, Oculoman Pachyonychia Ichtyosiforme, Pachyonychia Congenita with dibulofacial Syndrome, Oculomotor with Congenital Con Natal Teeth, Pachyonychia Congenita, Pachyonychia Con tractures and Muscle Atrophy, Oculosympathetic Palsy, genita Keratosis Disseminata Circumscripta (follicularis), ODD Syndrome, ODOD, Odontogenic Tumor, Odontotri Pachyonychia Congenita Jadassohn-Lewandowsky Type, chomelic Syndrome, OFD, OFD Syndrome, Ohio Type PAF with MSA, Paget’s Disease, Paget’s Disease of Bone, Amyloidosis (Type VII), OI, OI Congenita, OI Tarda, Old Paget’s Disease of the Breast, Paget’s Disease of the Nipple, field Syndrome, Oligohydramnios Sequence, Oligophrenia Paget’s Disease of the Nipple and Areola, Pagon Syndrome, Microphthalmos, Oligophrenic Polydystrophy, Olivoponto Painful Ophthalmoplegia, PAIS, Palatal Myoclonus, Palato cerebellar Atrophy, Olivopontocerebellar Atrophy with Oto-Digital Syndrome, Palatal-Oto-Digital Syndrome Type Dementia and Extrapyramidal Signs, Olivopontocerebellar I, Palatal-Oto-Digital Syndrome Type II, Pallister Syn Atrophy with Retinal Degeneration, Olivopontocerebellar drome, Pallister-Hall Syndrome, Pallister-Killian Mosaic Atrophy I, Olivopontocerebellar Atrophy II, Olivopontocer Syndrome, Pallister Mosaic Aneuploidy, Pallister Mosaic ebellar Atrophy III, Olivopontocerebellar Atrophy IV. Syndrome, Pallister Mosaic Syndrome Tetrasomy 12p, Pal Olivopontocerebellar Atrophy V. Ollier Disease, Ollier lister-W Syndrome, Palmoplantar Hyperkeratosis and Osteochondromatosis, Omphalocele-Visceromegaly-Mac Alopecia, Palsy, Pancreatic Fibrosis, Pancreatic Insuffi roglossia Syndrome, Ondine's Curse, Onion-Bulb Neuropa ciency and Bone Marrow Dysfunction, Pancreatic Ulcero thy, Onion Bulb Polyneuropathy, Onychoosteodysplasia, genic Tumor Syndrome, Panmyelophthisis, Panmyelopathy, Onychotrichodysplasia with Neutropenia, OPCA, OPCAI, Pantothenate kinase associated neurodegeneration (PKAN), OPCA II, OPCA III, OPCA IV, OPCA V, OPD Syndrome, Papillon-Lefevre Syndrome, Papillotonic Psuedotabes, OPD Syndrome Type I, OPD Syndrome Type II, OPD I Paralysis Periodica Paramyotonica, Paralytic Beriberi, Para Syndrome, OPD II Syndrome, Ophthalmoarthropathy, Oph lytic Brachial Neuritis, Paramedian Lower Lip Pits-Popliteal thalmoplegia-Intestinal Pseudoobstruction, Ophthalmople Pyerygium Syndrome, Paramedian Diencephalic Syndrome, gia, Pigmentary Degeneration of the Retina and Cadio Paramyeloidosis, Paramyoclonus Multiple, Paramyotonia myopathy, Ophthalmoplegia Plus Syndrome, Ophthal Congenita, Paramyotonia Congenita of Von Eulenburg, Par moplegia Syndrome, Opitz BBB Syndrome, Opitz, BBB/G kinson's disease, Paroxysmal Atrial Tachycardia, Paroxys Compound Syndrome, Opitz, BBBG Syndrome, Opitz-Frias mal Cold Hemoglobinuria, Paroxysmal Dystonia, Paroxys Syndrome, Opitz, G. Syndrome, Opitz G/BBB Syndrome, mal Dystonia Choreathetosis, Paroxysmal Kinesigenic Opitz Hypertelorism-Hypospadias Syndrome, Opitz-Kaveg Dystonia, Paroxysmal Nocturnal Hemoglobinuria, Paroxys gia Syndrome, Opitz, Oculogenitolaryngeal Syndrome, mal Normal Hemoglobinuria, Paroxysmal Sleep, Parrot Opitz Trigonocephaly Syndrome, Opitz Syndrome, Opso Syndrome, Parry Disease, Parry-Romberg Syndrome, Par clonus, OpSoclonus-Myoclonus, Opthamoneuromyelitis, Sonage-Turner Syndrome, Partial Androgen Insensitivity Optic Atrophy Polyneuropathy and Deafness, Optic Neu Syndrome, Partial Deletion of the Short Arm of Chromo roencephalomyelopathy, Optic Neuromyelitis, Opticomyeli some 4, Partial Deletion of the Short Arm of Chromosome tis, Optochiasmatic Arachnoiditis, Oral-Facial Clefts, Oral 5, Partial Deletion of Short Arm of Chromosome 9, Partial facial Dyskinesia, Oral Facial Dystonia, Oral-Facial-Digital Duplication 3q Syndrome, Partial Duplication 15q Syn Syndrome, Oral-Facial-Digital Syndrome Type I, Oral-Fa drome, Partial Facial Palsy With Urinary Abnormalities, cial-Digital Syndrome I, Oral-Facial-Digital Syndrome II, Partial Gigantism of Hands and Feet-Nevi-Hemihypertro Oral-Facial-Digital Syndrome III, Oral-Facial-Digital Syn phy-Macrocephaly, Partial Lipodystrophy, Partial Mono drome IV. Orbital Cyst with Cerebral and Focal Dermal somy of Long Arm of Chromosome 11, Partial Monosomy Malformations, Ornithine Carbamyl Transferase Deficiency, of the Long Arm of Chromosome 13, Partial Spinal Sensory Ornithine Transcarbamylase Deficiency, Orocraniodigital Syndrome, Partial Trisomy 11q, Partington Syndrome, PAT, Syndrome, Orofaciodigital Syndrome, Oromandibular Dys Patent Ductus Arteriosus, Pathological Myoclonus, Paucia tonia, Orthostatic Hypotension, Osler-Weber-Rendu disease, rticular-Onset Juvenile Arthritis, Paulitis, PBC, PBS, PC Osseous-Oculo-Dento Dysplasia, Osseous-Oculo-Dento Deficiency, PC Deficiency Group A, PC Deficiency Group D)ysplasia, Osteitis deformans, Osteochondrodystrophy B, PC, Eulenburg Disease, PCC Deficiency, 'PCH, PCLD, Deformans, Osteochondroplasia, Osteodysplasty of Melnick PCT, PD, PDA, PDH Deficiency, Pearson Syndrome Pyru and Needles, Osteogenesis Imperfect, Osteogenesis Imper vate Carboxylase Deficiency, Pediatric Obstructive Sleep fecta, Osteogenesis Imperfecta Congenita, Osteogenesis Apnea, Peeling Skin Syndrome, Pelizaeus-Merzbacher Dis Imperfecta Tarda, Osteohypertrophic Nevus Flammeus, ease, Pelizaeus-Merzbacher Brain Sclerosis, Peflagra-Cer Osteopathia Hyperostotica Scleroticans Multiplex Infanta ebellar Ataxia-Renal Aminoaciduria Syndrome, Pelvic Pain lis, Osteopathia Hyperostotica Scleroticans Multiplex Infan Syndrome, Pemphigus Vulgaris, Pena Shokeir II Syndrome, talis, Osteopathyrosis, Osteopetrosis, Osteopetrosis Autoso Pena Shokeir Syndrome Type II, Penile Fibromatosis, Penile mal Dominant Adult Type, Osteopetrosis Autosomal Fibrosis, Penile Induration, PentaX Syndrome, Pentalogy of Recessive Malignant Infantile Type, Osteopetrosis Mild Cantrell, Pentalogy Syndrome, Pentasomy X, PEPCK Defi Autosomal Recessive Intermediate Typ, Osteosclerosis Fra ciency, Pepper Syndrome, Perheentupa Syndrome, Periar gilis Generalisata, Osteosclerotic Myeloma, Ostium Primum ticular Fibrositis, Pericardial Constriction with Growth Fail Defect (endocardial cushion defects included), Ostium ure, Pericollagen Amyloidosis, Perinatal Polycystic Kidney Secundum Defect, OTC Deficiency, Oto Palato Digital Diseases, Perineal Anus, Periodic Amyloid Syndrome, Peri Syndrome, Oto-Palato-Digital Syndrome Type I, Oto-Pala odic Peritonitis Syndrome, Periodic Somnolence and Mor US 2007/0021589 A1 Jan. 25, 2007 34 bid Hunger, Periodic Syndrome, Peripheral Cystoid Degen Histiocytosis, Polyposis Familial, Polyposis Gardner Type, eration of the Retina, Peripheral Dysostosis-Nasal Polyposis Hamartomatous Intestinal, Polyposis-Osteomato Hypoplasia-Mental Retardation, Peripheral Neuritis, Periph sis-Epidermoid Cyst Syndrome, Polyposis Skin Pigmenta eral Neuropathy, Peritoneopericardial Diaphragmatic Her tion Alopecia and Fingernail Changes, Polyps and Spots nia, Pernicious Anemia, Peromelia with Micrognathia, Pero Syndrome, Polyserositis Recurrent, Polysomy Y. Polysyn neal Muscular Atrophy, Peroneal Nerve Palsy, Peroutka dactyly with Peculiar Skull Shape, Polysyndactyly-Dysmor Sneeze, Peroxisomal Acyl-CoA Oxidase, Peroxisomal Beta phic Craniofacies Greig Type, Pompe Disease, Pompe Dis Oxidation Disorders, Peroxisomal Bifunctional Enzyme, ease, Popliteal Pterygium Syndrome, Porcupine Man, Peroxisomal Thiolase, Peroxisomal Thiolase Deficiency, Porencephaly, Porencephaly, Porphobilinogen deaminase Persistent Truncus Arteriosus, Perthes Disease, Petit Mal (PBG-D), Porphyria, Porphyria Acute Intermittent, Porphy Epilepsy, Petit Mal Variant, Peutz-Jeghers Syndrome, Peutz ria ALA-D, Porphyria Cutanea Tarda, Porphyria Cutanea Touraine Syndrome, Peyronie Disease, Pfeiffer, Pfeiffer Tarda Hereditaria, Porphyria Cutanea Tarda Symptomatica, Syndrome Type I, PGA I, PGA II, PGA III, PGK, PH Type Porphyria Hepatica Variegate, Porphyria Swedish Type, I, PH Type I, Pharyngeal Pouch Syndrome, PHI) Short Porphyria Variegate, Porphyriam Acute Intermittent, Por Chain Acyl-CoA Dehydrogenase Deficiency, Phenylalanine phyrins, Porrigo Decalvans, Port Wine Stains, Portuguese Hydroxylase Deficiency, Phenylalaninemia, Phenylketo Type Amyloidosis, Post-Infective Polyneuritis, Postanoxic nuria, Phenylpyruvic Oligophrenia, Phocomelia, Phocome Intention Myoclonus, Postaxial Acrofacial Dysostosis, Post lia Syndrome, Phosphoenolpyruvate Carboxykinase Defi axial Polydactyly, Postencephalitic Intention Myoclonus, ciency, Phosphofructokinase Deficiency, Phosphoglycerate Posterior Corneal Dystrophy Hereditary, Posterior Thalamic Kinase Deficiency, Phosphoglycerokinase, Phosphorylase 6 Syndrome, Postmyelographic Arachnoiditis, Postnatal Cere Kinase Deficiency, Phosphorylase Deficiency Glycogen bral Palsy, Postoperative Cholestasis, Postpartum Galactor Storage Disease, Phosphorylase Kinase Deficiency of Liver, rhea-Amenorrhea Syndrome, Postpartum Hypopituitarism, Photic Sneeze Reflex, Photic Sneezing, Phototherapeutic Postpartum Panhypopituitary Syndrome, Postpartum Pan keratectomy, PHS, Physicist John Dalton, Phytanic Acid hypopituitarism, Postpartum Pituitary Necrosis, Postural Storage Disease, Pi Phenotype ZZ, PI, Pick Disease of the Hypotension, Potassium-Losing Nephritis, Potassium Loss Brain, Pick's Disease, Pickwickian Syndrome, Pierre Robin Syndrome, Potter Type I Infantile Polycystic Kidney Dis Anomalad, Pierre Robin Complex, Pierre Robin Sequence, eases, Potter Type III Polycystic Kidney Disease, PPH, PPS, Pierre Robin Syndrome, Pierre Robin Syndrome with Prader-Willi Syndrome, Prader-Labhart-Willi Fancone Syn Hyperphalangy and Clinodactyly, Pierre-Marie’s Disease, drome, Prealbumin Tyr-77 Amyloidosis, Preexcitation Syn Pigmentary Degeneration of Globus Pallidus Substantia drome, Pregnenolone Deficiency, Premature Atrial Contrac Nigra Red Nucleus, Pili Torti and Nerve Deafness, Pili tions, Premature Senility Syndrome, Premature Torti-Sensorineural Hearing Loss, Pituitary Dwarfism II, Supraventricular Contractions, Premature Ventricular Com Pituitary Tumor after Adrenalectomy, Pityriasis Pilaris, plexes, Prenatal or Connatal Neuroaxonal Dystrophy, Pres Pityriasis Rubra Pilaris, PJS, PKAN, PKD. PKD1, PKD2, enile Dementia, Presenile Macula Lutea Retinae Degenera PKD3, PKU, PKU1, Plagiocephaly, Plasma Cell Myeloma, tion, Primary Adrenal Insufficiency, Primary Plasma Cell Leukemia, Plasma Thromboplastin Component Agammaglobulinemias, Primary Aldosteronism, Primary Deficiency, Plasma Transglutaminase Deficiency, Plastic Alveolar Hypoventilation, Primary Amyloidosis, Primary Induration Corpora Cavernosa, Plastic Induration of the Anemia, Primary Beriberi, Primary Biliary, Primary Biliary Penis, PLD, Plicated Tongue, PLS, PMD, Pneumorenal Cirrhosis, Primary Brown Syndrome, Primary Carnitine Syndrome, PNH, PNM, PNP Deficiency, POD, POH, Poiki Deficiency, Primary Central Hypoventilation Syndrome, loderma Atrophicans and Cataract, Poikiloderma Congeni Primary Ciliary Dyskinesia Kartagener Type, Primary Cuta tale, Poland Anomaly, Poland Sequence, Poland Syndactyly, neous Amyloidosis, Primary Dystonia, Primary Failure Poland Syndrome, Poliodystrophia Cerebri Progressiva, Adrenocortical Insufficiency, Primary Familial Hypoplasia Polyarthritis Enterica, Polyarteritis Nodosa, Polyarticular of the Maxilla, Primary Hemochromatosis, Primary Hyper Onset Juvenile Arthritis Type I, Polyarticular-Onset Juvenile hidrosis, Primary Hyperoxaluria Type I, Primary Hyper Arthritis Type II, Polyarticular-Onset Juvenile Arthritis oxaluria Type 1 (PH1), Primary Hyperoxaluria Type 1, Types I and II, Polychondritis, Polycystic Kidney Disease, Primary Hyperoxaluria Type II, Primary Hyperoxaluria Polycystic Kidney Disease Medullary Type, Polycystic Type III, Primary Hypogonadism, Primary Intestinal Lym Liver Disease, Polycystic Ovary Disease, Polycystic Renal phangiectasia, Primary Lateral Sclerosis, Primary Nonhe Diseases, Polydactyly-Joubert Syndrome, Polydysplastic reditary Amyloidosis, Primary Obliterative Pulmonary Vas Epidermolysis Bullosa, Polydystrophia Oligophrenia, Poly cular Disease, Primary Progressive Multiple Sclerosis, dystrophic Dwarfism, Polyglandular Autoimmune Syn Primary Pulmonary Hypertension, Primary Reading Dis drome Type III, Polyglandular Autoimmune Syndrome Type ability, Primary Renal Glycosuria, Primary Sclerosing Cho II, Polyglandular Autoimmune Syndrome Type I, Polyglan langitis, Primary Thrombocythemia, Primary Tumors of dular Autoimmune Syndrome Type II, Polyglandular Defi Central Nervous System, Primary Visual Agnosia, Procto ciency Syndrome Type II, Polyglandular Syndromes, Poly colitis Idiopathic, Proctocolitis Idiopathic, Progeria of morphic Macula Lutea Degeneration, Polymorphic Macular Adulthood, Progeria of Childhood, Progeroid Nanism, Prog Degeneration, Polymorphism of Platelet Grlycoprotien Ib. eriod Short Stature with Pigmented Nevi, Progeroid Syn Polymorphous Corneal Dystrophy Hereditary, Polymyalgia drome of De Barsy, Progressive Autonomic Failure with Rheumatica, Polymyositis and Dermatomyositis, Primary Multiple System Atrophy, Progressive Bulbar Palsy, Pro Agammaglobulinemia, Polyneuritis Peripheral, Polyneur gressive Bulbar Palsy Included, Progressive Cardiomyo opathy-Deafness-Optic Atrophy, Polyneuropathy Periph pathic Lentiginosis, Progressive Cerebellar Ataxia Familial, eral, Polyneuropathy and Polyradiculoneuropathy, Polyos Progressive Cerebral Poliodystrophy, Progressive Choroidal totic Fibrous Dysplasia, Polyostotic Sclerosing Atrophy, Progressive Diaphyseal Pysplasia, Progressive US 2007/0021589 A1 Jan. 25, 2007

Facial Hemiatrophy, Progressive Familial Myoclonic Epi Refsum Disease, Refsum's Disease, Regional Enteritis, lepsy, Progressive Hemifacial Atrophy, Progressive Hypo Reid-Barlow's syndrome, Reifenstein Syndrome, Reiger erythemia, Progressive Infantile Poliodystrophy, Progres Anomaly-Growth Retardation, Reiger Syndrome, Reimann sive Lenticular Degeneration, Progressive Lipodystrophy, Periodic Disease, Reimann's Syndrome, Reis-Bucklers Cor Progressive Muscular Dystrophy of Childhood, Progressive neal Dystrophy, Reiter's Syndrome, Relapsing Guillain Myoclonic Epilepsy, Progressive Osseous Heteroplasia, Barre Syndrome, Relapsing-Remitting Multiple Sclerosis, Progressive Pallid Degeneration Syndrome, Progressive Renal Agenesis, Renal Dysplasia-Blindness Hereditary, Spinobulbar Muscular Atrophy, Progressive Supranuclear Renal Dysplasia-Retinal Aplasia Loken-Senior Type, Renal Palsy, Progressive Systemic Sclerosis, Progressive Tapeto Glycosuria, Renal Glycosuria Type A, Renal Glycosuria choroidal Dystrophy, Oxidase Deficiency, Propionic Type B, Renal Glycosuria Type O, Renal-Oculocerebrodys Acidemia, Type I (PCCA Deficiency), trophy, Renal-Retinal Dysplasia with Medullary Cystic Dis Propionic Acidemia Type II (PCCB Deficiency), Propionyl ease, Renal-Retinal Dystrophy Familial, Renal-Retinal Syn CoA Carboxylase Deficiency, Protanomaly, Protanopia, Pro drome, Rendu-Osler-Weber Syndrome, Respiratory tein-Losing Enteropathy Secondary to Congestive Heart Acidosis, Respiratory Chain Disorders, Respiratory Myo Failure, Proteus Syndrome, Proximal Deletion of 4q clonus, Restless Legs. Syndrome, Restrictive Cardiomyopa Included, PRP PRS, Prune Belly Syndrome, PS, Pseudo thy, Retention Hyperlipemia, Rethore Syndrome (obsolete), Hurler Polydystrophy, Pseudo-Polydystrophy, Pseudoacan Reticular Dysgenesis, Retinal Aplastic-Cystic Kidneys-Jou thosis Nigricans, Pseudoachondroplasia, Pseudocholinest bert Syndrome, Retinal Cone Degeneration, Retinal Cone erase Deficiency, Pseudogout Familial, Pseudohemophilia, Dystrophy, Retinal Cone-Rod Dystrophy, Retinitis Pigmen Pseudohermaphroditism, Pseudohermaphroditism-Nephron tosa, Retinitis Pigmentosa and Congenital Deafness, Ret Disorder-Wilm's Tumor, Pseudohypertrophic Muscular inoblastoma, Retinol Deficiency, Retinoschisis, Retinoschi Dystrophy, Pseudohypoparathyroidism, Pseudohypophos sis Juvenile, Retraction Syndrome, Retrobulbar Neuropathy, phatasia, Pseudopolydystrophy, Pseudothalidomide Syn Retrolenticular Syndrome, Rett Syndrome, Reverse Coarc drome, Pseudoxanthoma Elasticum, Psoriasis, Psorosper tion, Reye Syndrome, Reye's Syndrome, RGS, Rh Blood mosis Follicularis, PSP, PSS, Psychomotor Convulsion, Factors, Rh Disease, Rh Factor Incompatibility, Rh Incom Psychomotor Epilepsy, Psychomotor Equivalent Epilepsy, patibility, Rhesus Incompatibility, Rheumatic Fever, Rheu PTC Deficiency, Pterygium, Pterygium Colli Syndrome, matoid Arthritis, Rheumatoid Myositis, Rhinosinusogenic Pterygium Universale, Pterygolymphangiectasia, Pulmo Cerebral Arachnoiditis, Rhizomelic Chondrodysplasia nary Atresia, Pulmonary Lymphangiomyomatosis, Pulmo Punctata (RCDP), Acatalasemia, Classical Refsum disease, nary Stenosis, Pulmonic Stenosis-Ventricular Septal Defect, RHS, Rhythmical Myoclonus, Rib Gap Defects with Micro Pulp Stones, Pulpal Dysplasia, Pulseless Disease, Pure gnathia, Ribbing Disease (obsolete), Ribbing Disease, Rich Alymphocytosis, Pure Cutaneous Histiocytosis, Purine ner-Hanhart Syndrome, Rieger Syndrome, Rieter's Syn Nucleoside Phosphorylase Deficiency, Purpura Hemor drome, Right Ventricular Fibrosis, Riley-Day Syndrome, rhagica, Purtilo Syndrome, PXE, PXE Dominant Type, PXE Riley-Smith syndrome, Ring Chromosome 14, Ring Chro Recessive Type, Pycnodysostosis, Pyknodysostosis, Pyk mosome 18, Ring 4, Ring 4 Chromosome, Ring 6. Ring 6 noepilepsy, Pyroglutamic Aciduria, Pyroglutamicaciduria, Chromosome, Ring 9, Ring 9 Chromosome R9, Ring 14. Pyrroline Carboxylate pehydrogenase Deficiency, Pyruvate Ring 15, Ring 15 Chromosome (mosaic pattern), Ring 18, Carboxylase Deficiency, Pyruvate Carboxylase Deficiency Ring Chromosome 18, Ring 21, Ring 21 Chromosome, Ring Group A, Pyruvate Carboxylase Deficiency Group B, Pyru 22, Ring 22 Chromosome, Ritter Disease, Ritter-Lyell Syn vate Dehydrogenase Deficiency, Pyruvate Kinase Defi drome, RLS, RMSS, Roberts SC-Phocomelia Syndrome, ciency, q25-qter, q26 or q27-qter, q31 or 32-qter, QT Pro Roberts Syndrome, Roberts Tetraphocomelia Syndrome, longation with Extracellular Hypohypocalcinemia, QT Robertson's Ectodermal Dysplasias, Robin Anomalad, Prolongation without Congenital Deafness, QT Prolonged Robin Sequence, Robin Syndrome, Robinow Dwarfism, with Congenital Deafness, Quadriparesis of Cerebral Palsy, Robinow Syndrome, Robinow Syndrome Dominant Form, Quadriplegia of Cerebral Palsy, Quantal Squander, Quantal Robinow Syndrome Recessive Form, Rod myopathy, Roger Squander, ra, ré, r14, r 18, r21, r22, Rachischisis Posterior, Disease, Rokitansky's Disease, Romano-Ward Syndrome, Radial Aplasia-Amegakaryocytic Thrombocytopenia, Romberg Syndrome, Rootless Teeth, Rosenberg-Chutorian Radial Aplasia-Thrombocytopenia Syndrome, Radial Nerve Syndrome, Rosewater Syndrome, Rosselli-Gulienatti Syn Palsy, Radicular Neuropathy Sensory, Radicular Neuropathy drome, Rothmund-Thomson Syndrome, Roussy-Levy Syn Sensory Recessive, Radicular Dentin Dysplasia, Rapid-on drome, RP RSX-Linked, RS, RSDS, RSH Syndrome, RSS, set Dystonia-parkinsonism, Rapp-Hodgkin Syndrome, RSTS, RTS, Rubella Congenital, Rubinstein Syndrome, Rapp-Hodgkin (hypohidrotic) Ectodermal Dysplasia Syn Rubinstein-Taybi Syndrome, Rubinstein Taybi Broad drome, Rapp-Hodgkin Hypohidrotic Ectodermal Dyspla Thumb-Hallux syndrome, Rufous Albinism, Ruhr's Syn sias, Rare hereditary ataxia with polyneuritic changes and drome, Russell's Diencephalic Cachexia, Russell's Syn deafness caused by a defect in the enzyme phytanic acid drome, Russell Syndrome, Russell-Silver Dwarfism, Rus hydroxylase, Rautenstrauch-Wiedemann Syndrome, Rau sell-Silver Syndrome, Russell-Silver Syndrome X-linked, tenstrauch-Wiedemann Type Neonatal Progeria, Raynaud's Ruvalcaba-Myhre-Smith syndrome (RMSS), Ruvalcaba Phenomenon, RDP. Reactive Functional Hypoglycemia, Syndrome, Ruvalcaba Type Osseous Dysplasia with Mental Reactive Hypoglycemia Secondary to Mild Diabetes, Reces Retardation, Sacral Regression, Sacral Agenesis Congenital, sive Type Kenny-Caffe Syndrome, Recklin Recessive Type SAE, Saethre-Chotzen Syndrome, Sakati, Sakati Syndrome, Myotonia Congenita, Recklinghausen Disease, Recto Sakati-Nyhan Syndrome, Salaam Spasms, Salivosudoripa perineal Fistula, Recurrent Vomiting, Reflex Neurovascular rous Syndrome, Salzman Nodular Corneal Dystrophy, Sand Dystrophy, Reflex Sympathetic Dystrophy Syndrome, hoff Disease, Sanfilippo Syndrome, Sanfilippo Type A, Refractive Errors, Refractory Anemia, Refrigeration Palsy, Sanfilippo Type B, Santavuori Disease, Santavuori-Haltia US 2007/0021589 A1 Jan. 25, 2007 36

Disease, Sarcoid of Boeck, Sarcoidosis, Sathre-chotzen, dian Syndrome, Shwachman-Diamond Syndrome, Shwach Saturday Night Palsy, SBMA, SC Phocomelia Syndrome, man Syndrome, Shwachman-Diamond-Oski Syndrome, SC Syndrome, SCA3, SCAD Deficiency, SCAD Deficiency Shwachmann Syndrome, Shy Drager Syndrome, Shy-Ma Adult-Onset Localized, SCAD Deficiency Congenital Gen gee Syndrome, SI Deficiency, Sialidase Deficiency, Sialido eralized, SCAD, SCADH-Deficiency, Scalded Skin Syn sis Type I Juvenile, Sialidosis Type II Infantile, Sialidosis, drome, Scalp Defect Congenital, Scaphocephaly, Scapula Sialolipidosis, Sick Sinus Syndrome, Sickle Cell Anemia, Elevata, Scapuloperoneal myopathy, Scapuloperoneal Mus Sickle Cell Disease, Sickle Cell-Hemoglobin C Disease, cular Dystrophy, Scapuloperoneal Syndrome Myopathic Sickle Cell-Hemoglobin D Disease, Sickle Cell-Thalas Type, Scarring Bullosa, SCHAD, Schaumann's Disease, semia Disease, Sickle Cell Trait, Sideroblastic Anemias, Scheie Syndrome, Schereshevkii-Turner Syndrome, Sideroblastic Anemia, Sideroblastosis, SIDS, Siegel-Cattan Schilder Disease, Schilder Encephalitis, Schilder's Disease, Mamou Syndrome, Siemens-Bloch type Pigmented Derma Schindler Disease Type I (Infantile Onset), Schindler Dis tosis, Siemens Syndrome, Siewering-Creutzfeldt Disease, ease Infantile Onset, Schindler Disease, Schindler Disease Siewert Syndrome, Silver Syndrome, Silver-Russell Dwarf Type II (Adult Onset), Schinzel Syndrome, Schinzel ism, Silver-Russell Syndrome, Simmond's Disease, Simons Giedion Syndrome, Schinzel Acrocallosal Syndrome, Schin Syndrome, Simplex Epidermolysis Bullosa, Simpson Dys Zel-Giedion Midface-Retraction Syndrome, Schizencephaly, morphia Syndrome, Simpson-Golabi-Behmel Syndrome, Schmid Type Metaphyseal Chondrodysplasia, Schmid Sinding-Larsen-Johansson Disease, Singleton-Merten Syn Metaphyseal Dysostosis, Schmid-Fraccaro Syndrome, drome, Sinus Arrhythmia, Sinus Venosus, Sinus tachycardia, Schmidt Syndrome, Schopf-Schultz-Passarge Syndrome, Sirenomelia Sequence, Sirenomelus, Situs Inversus Bron Schueller-Christian Disease, Schut-Haymaker Type, chiectasis and Sinusitis, SJA Syndrome, Sjogren Larsson Schwartz-Jampel-Aberfeld Syndrome, Schwartz-Jampel Syndrome Ichthyosis, Sjogren Syndrome, Sjögren's Syn Syndrome Types 1A and 1B, Schwartz-Jampel Syndrome, drome, SJS, Skeletal dysplasia, Skeletal Dysplasia Weis Schwartz-Jampel Syndrome Type 2, SCID, Scleroderma, mann Netter Stuhl Type, Skin Peeling Syndrome, Skin Sclerosis Familial Progressive Systemic, Sclerosis Diffuse Neoplasms, Skull Asymmetry and Mild Retardation, Skull Familial Brain, Scott Craniodigital Syndrome With Mental Asymmetry and Mild Syndactyly, SLE, Sleep Epilepsy, Retardation, Scrotal Tongue, SCS, SD, SDS, SDYS, Sea Sleep Apnea, SLO, Sly Syndrome, SMA, SMA Infantile sonal Conjunctivitis, Sebaceous Nevus Syndrome, Seba Acute Form, SMA I, SMA III, SMA type I, SMA type II, ceous nevus, Seborrheic Keratosis, Seborrheic Warts, Seckel SMA type III, SMA3, SMAX1, SMCR, Smith Lemli Opitz Syndrome, Seckel Type Dwarfism, Second Degree Congeni Syndrome, Smith Magenis Syndrome, Smith-Magenis tal Heart Block, Secondary Amyloidosis, Secondary Ble Chromosome Region, Smith-McCort Dwarfism, Smith pharospasm, Secondary Non-tropical Sprue, Secondary Opitz-Inborn Syndrome, Smith Disease, Smoldering Brown Syndrome, Secondary Beriberi, Secondary General Myeloma, SMS, SNE, Sneezing From Light Exposure, ized Amyloidosis, Secondary Dystonia, Secretory Compo Sodium valproate, Solitary Plasmacytoma of Bone, Sorsby nent Deficiency, Secretory IgA Deficiency, SED Tarda, SED Disease, Sotos Syndrome, Souques-Charcot Syndrome, Congenital, SEDC, Segmental linear achromic nevus, Seg South African Genetic Porphyria, Spasmodic Dysphonia, mental Dystonia, Segmental Myoclonus, Seip Syndrome, Spasmodic Torticollis, Spasmodic Wryneck, Spastic Cere Seitelberger Disease, Seizures, Selective Deficiency of IgG bral Palsy, Spastic Colon, Spastic Dysphonia, Spastic Subclasses, Selective Mutism, Selective Deficiency of IgG Paraplegia, SPD Calcinosis, Specific Antibody Deficiency Subclass, Selective IgM Deficiency, Selective Mutism, with Normal Immunoglobulins, Specific Reading Disability, Selective IgA Deficiency, Self-Healing Histiocytosis, Semi SPH2, Spherocytic Anemia, Spherocytosis, Spherophakia lobar Holoprosencephaly, Seminiferous Tubule Dysgenesis, Brachymorphia Syndrome, Sphingomyelin Lipidosis, Sph Senile Retinoschisis, Senile Warts, Senior-Loken Syndrome, ingomyelinase Deficiency, Spider fingers, Spielmeyer-Vogt Sensory Neuropathy Hereditary Type I, Sensory Neuropathy Disease, Spielmeyer-Vogt-Batten Syndrome, Spina Bifida, Hereditary Type II, Sensory Neuropathy Hereditary Type I, Spina Bifida Aperta, Spinal Arachnoiditis, Spinal Arterio Sensory Radicular Neuropathy, Sensory Radicular Neuropa venous Malformation, Spinal Ataxia Hereditofamilial, Spi thy Recessive, Septic Progressive Granulomatosis, Septo nal and Bulbar Muscular Atrophy, Spinal Diffuse Idiopathic Optic Dysplasia, Serous Circumscribed Meningitis, Serum Skeletal Hyperostosis, Spinal DISH, Spinal Muscular Atro Protease Inhibitor Deficiency, Serum Carnosinase Defi phy, Spinal Muscular Atrophy All Types, Spinal Muscular ciency, Setleis Syndrome. Severe Combined Immunodefi Atrophy Type ALS, Spinal Muscular Atrophy-Hypertrophy ciency, Severe Combined Immunodeficiency with Adenos of the Calves, Spinal Muscular Atrophy Type I, Spinal ine Deaminase Deficiency, Severe Combined Muscular Atrophy Type III, Spinal Muscular Atrophy type 3. Immunodeficiency (SCID), Sex Reversal, Sexual Infanti Spinal Muscular Atrophy-Hypertrophy of the Calves, Spinal lism, SGB Syndrome. Sheehan Syndrome, Shields Type Ossifying Arachnoiditis, Spinal Stenosis, Spino Cerebellar Dentinogenesis Imperfecta, Shingles, varicella-Zoster virus, Ataxia, Spinocerebellar Atrophy Type I, Spinocerebellar Ship Beriberi, SHORT Syndrome, Short Arm 18 Deletion Ataxia Type I (SCAI), Spinocerebellar Ataxia Type II Syndrome, Short Chain Acyl CoA Dehydrogenase Defi (SCAII), Spinocerebellar Ataxia Type III (SCAIII), Spinoc ciency, Short Chain Acyl-CoA Dehydrogenase (SCAD) erebellar Ataxia Type III (SCA 3), Spinocerebellar Ataxia Deficiency, Short Stature and Facial Telangiectasis, Short Type IV (SCAIV), Spinocerebellar Ataxia Type V (SCAV), Stature Facial/Skeletal Anomalies-Retardation-Macrodon Spinocerebellar Ataxia Type VI (SCAVI), Spinocerebellar tia, Short Stature-Hyperextensibility-Rieger Anomaly Ataxia Type VII (SCAVII), Spirochetal Jaundice, Splenic Teething Delay, Short Stature-Onychodysplasia, Short Stat Agenesis Syndrome, Splenic Ptosis, Splenoptosis, Split ure Telangiectatic Erythema of the Face, SHORT Syndrome, Hand Deformity-Mandibulofacial Dysostosis, Split Hand Shoshin Beriberi, Shoulder girdle syndrome, Shprintzen Deformity, Spondyloarthritis, Spondylocostal Dysplasia— Goldberg Syndrome, Shulman Syndrome, Shwachman-Bo Type I, Spondyloepiphyseal Dysplasia Tarda, Spondylotho US 2007/0021589 A1 Jan. 25, 2007 37 racic Dysplasia, Spondylotic Caudal Radiculopathy, Sponge phy, Teschler-Nicola/Killian Syndrome, Tethered Spinal Kidney, Spongioblastoma Multiforme, Spontaneous Cord Syndrome, Tethered Cord Malformation Sequence, Hypoglycemia, Sprengel Deformity, Spring Ophthalmia, Tethered Cord Syndrome, Tethered Cervical Spinal Cord SRS, ST, Stale Fish Syndrome, Staphyloccal Scalded Skin Syndrome, Tetrahydrobiopterin Deficiencies, Tetrahydro Syndrome, Stargardt’s Disease, Startle Disease, Status Epi biopterin Deficiencies, Tetralogy of Fallot, Tetraphocome lepticus, Steele-Richardson-Olszewski Syndrome, Steely lia-Thrombocytopenia Syndrome, Tetrasomy Short Arm of Hair Disease, Stein-Leventhal Syndrome, Steinert Disease, Chromosome 9, Tetrasomy 9p, Tetrasomy Short Arm of Stengel’s Syndrome, Stengel-Batten-Mayou-Spielmeyer Chromosome 18, Thalamic Syndrome, Thalamic Pain Syn Vogt-Stock Disease, Stenosing Cholangitis, Stenosis of the drome, Thalamic Hyperesthetic Anesthesia, Thalassemia Lumbar Vertebral Canal, Stenosis, Steroid Sulfatase Defi Intermedia, Thalassemia Minor, Thalassemia Major. Thia ciency, Stevanovic's Ectodermal Dysplasias, Stevens mine Deficiency. Thiamine-Responsive Maple Syrup Ulrine Johnson Syndrome, STGD, Stickler Syndrome, Stiff-Man Disease. Thin-Basement-Membrane Nephropathy. Thiolase Syndrome, Stiff Person Syndrome, Still's Disease, Stilling deficiency, RCDP. Acyl-CoA dihydroxyacetonephqsphate Turk-Duane Syndrome, Stillis Disease, Stimulus-Sensitive acyltransferase. Third and Fourth Pharyngeal Pouch Syn Myoclonus, Stone Man Syndrome, Stone Man, Streeter drome. Third Degree Congenital (Complete) Heart Block, Anomaly, Striatonigral Degeneration Autosomal Dominant Thomsen Disease, Thoracic-Pelvic-Phalangeal Dystrophy, Type, Striopallidodentate Calcinosis, Stroma, Descemet's Thoracic Spinal Canal, Thoracoabdominal Syndrome, Tho Membrane, Stromal Corneal Dystrophy, Struma Lym racoabdominal Ectopia Cordis Syndrome, Three M Syn phomatosa, Sturge-Kalischer-Weber Syndrome, Sturge drome, Three-MSlender-Boned Nanism, Thrombasthenia of Weber Syndrome, Sturge-Weber Phakomatosis, Subacute Glanzmann and Naegeli, Thrombocythemia Essential, Necrotizing Encephalomyelopathy, Subacute Spongiform Thrombocytopenia-Absent Radius Syndrome. Thrombocy Encephalopathy, Subacute Necrotizing Encephalopathy, topenia-Hemangioma Syndrome, Thrombocytopenia-Ab Subacute Sarcoidosis, Subacute Neuronopathic, Subaortic sent Radii Syndrome, Thrombophilia Hereditary Due to AT Stenosis, Subcortical Arteriosclerotic Encephalopathy, Sub III, Thrombotic Thrombocytopenic Purpura, Thromboulcer endocardial Sclerosis, Succinylcholine Sensitivity, Sucrase ative Colitis, Thymic Dysplasia with Normal Immunoglo Isomaltase Deficiency Congenital. Sucrose-Isomaltose Mal bulins, Thymic Agenesis, Thymic Aplasia DiGeorge Type, absorption Congenital. Sucrose Intolerance Congenital, Thymic Hypoplasia Agammaglobulinemias Primary Sudanophilic Leukodystrophy ADL, Sudanophilic Leukod Included, Thymic Hypoplasia DiGeorge Type, Thymus Con ystrophy Pelizaeus-Merzbacher Type, Sudanophilic Leu genital Aplasia, Tic Douloureux, Tics, Tinel’s syndrome, kodystrophy Included, Sudden Infant Death Syndrome, Tolosa Hunt Syndrome, Tonic Spasmodic Torticollis, Tonic Sudeck's Atrophy, Sugio-Kajii Syndrome, Summerskill Pupil Syndrome, Tooth and Nail Syndrome, Torch Infection, Syndrome, Summit Acrocephalosyndactyly, Summitt's TORCH Syndrome, Torsion Dystonia, Torticollis, Total AcrocephaloSyndactyly, Summitt Syndrome, Superior Lipodystrophy, Total anomalous pulmonary venous connec Oblique Tendon Sheath Syndrome, Suprarenal glands, Sup tion, Touraine's Aphthosis, Tourette Syndrome, Tourette's ravalvular Aortic Stenosis, Supraventricular tachycardia, disorder, Townes-Brocks Syndrome, Townes Syndrome, Surdicardiac Syndrome, Surdocardiac Syndrome, SVT, Toxic Paralytic Anemia, Toxic Epidermal Necrolysis, Toxo Sweat Gland Abscess, Sweating Gustatory Syndrome, pachyosteose Diaphysaire Tibio-Peroniere, Toxopachyos Sweet Syndrome, Swiss Cheese Cartilage Syndrome, Syn teose, Toxoplasmosis. Other Agents Rubella Cytomegalovi dactylic Oxycephaly, Syndactyly Type I with Microcephaly rus Herpes Simplex, Tracheoesophageal Fistula with or and Mental Retardation, Syndromatic Hepatic Ductular without Esophageal Atresia, Tracheoesophageal Fistula, Hypoplasia, Syringomyelia, Systemic Aleukemic Reticu Transient neonatal myasthenia gravis, Transitional Atrioven loendotheliosis, Systemic Amyloidosis, Systemic Carnitine tricular Septal Defect, Transposition of the great arteries, Deficiency, Systemic Elastorrhexis, Systemic Lupus Erythe Transtelephonic Monitoring, Transthyretin. -30 matosus, Systemic Mast Cell Disease, Systemic Mastocy Amyloidosis (Type I), Trapezoidocephaly-Multiple Synos tosis, Systemic-Onset Juvenile Arhritis, Systemic Sclerosis, tosis Syndrome, Treacher Collins Syndrome, Treacher Col Systopic Spleen, T-Lymphocyte Deficiency, Tachyalimenta lins-Franceschetti Syndrome 1, Trevor Disease, Triatrial tion Hypoglycemia, Tachycardia, Takahara syndrome, Taka Heart, Tricho-Dento-Osseous Syndrome, Trichodento yasu Disease, Takayasu Arteritis, Talipes Calcaneus, Talipes Osseous Syndrome, Trichopoliodystrophy, Trichorhinopha Equinovarus, Talipes Equinus, Talipes Varus, Talipes Val langeal Syndrome, Trichorhinophalangeal Syndrome, Tri gus, Tandem Spinal Stenosis, Tangier Disease, Tapetoretinal cuspid atresia, Triflinctional Protein Deficiency, Trigeminal Degeneration, TAR Syndrome, Tardive Dystonia, Tardive Neuralgia, Triglyceride Storage Disease Impaired Long Muscular Dystrophy, Tardive Dyskinesia, Tardive Oral Dys Chain Fatty Acid Oxidation, Trigonitis, Trigonocephaly, kinesia, Tardive Dystonia, Tardy Ulnar Palsy, Target Cell Trigonocephaly Syndrome, Trigonocephaly “C” Syndrome, Anemia, Tarsomegaly, Tarui Disease, TAS Midline Defects , Triphalangeal Thumbs-Hypoplastic Included, TAS Midline Defect, Tay Sachs Sphingolipidosis, Distal Phalanges-Onychodystrophy, Triphalangeal Thumb Tay Sachs Disease, Tay Syndrome Ichthyosis, Tay Sachs Syndrome, Triple Symptom Complex of Behcet, Triple X Sphingolipidosis, Tay Syndrome Ichthyosis, Taybi Syn Syndrome, Triplo X Syndrome, Triploid Syndrome, Trip drome Type I, Taybi Syndrome, TCD, TCOF1, TCS, TD, loidy, Triploidy Syndrome, Trismus-Pseudocamptodactyly TDO Syndrome, TDO-I, TDO-II, TDO-III, Telangiectasis, Syndrome, Trisomy, Trisomy G Syndrome, Trisomy X, Telecanthus with Associated Abnormalities, Telecanthus Trisomy 6q Partial, Trisomy 6q Syndrome Partial, Trisomy Hypospadias Syndrome, Temporal Lobe Epilepsy, Temporal 9 Mosaic, Trisomy 9PSyndrome (Partial) Included, Trisomy Arteritis/Giant Cell Arteritis, Temporal Arteritis, TEN, Ten 11q Partial, Trisomy 14 Mosaic, Trisomy 14 Mosaicism don Sheath Adherence Superior Obliqu, Tension Myalgia, Syndrome, Trisomy 21 Syndrome, Trisomy 22 Mosaic, Terminal Deletion of 4q Included, Terrian Corneal Dystro Trisomy 22 Mosaicism Syndrome, TRPS, TRPS1, TRPS2, US 2007/0021589 A1 Jan. 25, 2007

TRPS3, True Hermaphroditism, Truncus arteriosus, Tryp Radial, Vertebral Ankylosing Hyperostosis, Very Early tophan Malabsorption, Tryptophan Pyrrolase Deficiency, Onset Huntington's Disease, Very Long Chain Acyl-CoA TS, TTP, TnTS, Tuberous Sclerosis, Tubular Ectasia, Turcot Dehydrogenase (VLCAD) Deficiency, Vestibular Schwan Syndrome, Turner Syndrome, Turner-Kieser Syndrome, noma, Vestibular Schwannoma Neurofibromatosis, Vestibu Turner Phenotype with Normal (Karyotype), locerebellar, Virchow's Oxycephaly, Visceral Xanthogranu Turner-Vamy Syndrome, Turricephaly, Twin-Twin Transfu lomatosis, Visceral Xantho-Granulomatosis, Visceral sion Syndrome, Twin-to-Twin Transfusion Syndrome, Type myopathy-Extemal Ophthalmoplegia, Visceromegaly-Um A, Type B, Type AB, Type O, Type I Diabetes, Type I bilical Hernia-Macroglossia Syndrome, Visual Amnesia, Familial Incomplete Male, Type I Familial Incomplete Male Vitamin A Deficiency, Vitamin B-1 Deficiency, Vitelline Pseudohermaphroditism, Type I Gaucher Disease, Type I Macular Dystrophy, Vitiligo, Vitiligo Capitis, Vitreoretinal (PCCA Deficiency). Type I Tyrosinemia, Type II Gaucher Dystrophy, VKC, VKH Syndrome, VLCAD, Vogt Syn Disease, Type II Histiocytosis, Type II (PCCB Deficiency), drome, Vogt Cephalosyndactyly, Vogt Koyanagi Harada Type II Tyrosinnemia, Type IIA Distal Artirogryposis Mul Syndrome, Von Bechterew-Strumpell Syndrome, Von tiplex Congenita, Type III Gaucher Disease, Type III Eulenburg Paramyotonia Congenita, Von Frey's Syndrome, Tyrosinemia, Type III Dentinogenesis Imperfecta, Typical Von Gierke Disease, Von Hippel-Lindau Syndrome, Von Retinoschisis, Tyrosinase Negative Albinism (Type I), Tyro Mikulicz. Syndrome, Von Recklinghausen Disease, Von sinase Positive Albinism (Type II), Tyrosinemia type 1 acute Willebrandt Disease, VP. Vrolik Disease (Type II), VSD, form, Tyrosinemia type 1 chronic form, Tyrosinosis, UCE, Vulgaris Type Disorder of Cornification, Vulgaris Type Ulcerative Colitis, Ulcerative Colitis Chronic Non-Specific, Ichthyosis, W Syndrome, , Ulnar-Mammary Syndrome, Ulnar-Mammary Syndrome of Waardenburg-Klein Syndrome, Waardenburg Syndrome Pallister, Ulnar Nerve Palsy, UMS, Unclassified FODs, Type I (WS1), Waardenburg Syndrome Type II (WS2), Unconjugated Benign Bilirubinemiav. Underactivity of Par Waardenburg Syndrome Type IIA (WS2A), Waardenburg athyroid, Unilateral Ichthyosiform Erythroderma with Ipsi Syndrome Type IIB (WS2B), Waardenburg Syndrome Type lateral Malformations Limb, Unilateral Chondromatosis, III (WS3), Waardenburg Syndrome Type IV (WS4), Unilateral Defect of Pectoralis Muscle and Syndactyly of the Waelsch's Syndrome, WAGR Complex, WAGR Syndrome, Hand, Unilateral Hemidysplasia Type, Unilateral Megalen Waldenstroems Macroglobulinemia, Waldenstrom's Pur cephaly, Unilateral Partial Lipodystrophy, Unilateral Renal pura, Waldenstrom's Syndrome, Waldmann Disease, Agenesis, Unstable Colon, Unverricht Disease, Unverricht Walker-Warburg Syndrome, Wandering Spleen, Warburg Lundborg Disease, Unverricht-Lundborg-Laf Disease, Syndrome, Warm Antibody Hemolytic Anemia, Warm Unverricht Syndrome, Upper Limb Cardiovascular Syn Reacting Antibody Disease, Wartenberg Syndrome, WAS, drome (Holt-Oram), Upper Motor Neuron Disease, Upper Water on the Brain, Watson Syndrome, Watson-Alagile Airway Apnea, Defects or Disorders, Urea Cycle Syndrome, Waterhouse-Friderichsen syndrome, Waxy Dis Disorder Arginase Type, Urea Cycle Disorder Arginino ease, WBS. Weaver Syndrome, Weaver-Smith Syndrome, Succinase Type, Urea Cycle Disorders Carbamyl Phosphate Weber-Cockayne Disease, Wegener's Granulomatosis, Weil Synthetase Type, Urea Cycle Disorder Citrullinemia Type, Disease, Weil Syndrome, Weill-Marchesani, Weill Urea Cycle Disorders N-Acrtyl Glutamate Synthetase Typ, Marchesani Syndrome, Weill-Reyes Syndrome, Weismann Urea Cycle Disorder OTC Type, Urethral Syndrome, Ure Netter-Stuhl Syndrome, Weissenbacher-Zweymuller Syn thro-Oculo-Articular Syndrome, Uridine Diphosphate Glu drome, Wells Syndrome, Wenckebach, Werdnig-Hoflinan curonosyltransferase Severe Def. Type I, Urinary Tract Disease, Werdnig-Hoffman Paralysis, Weribofs Disease, Defects, Urofacial Syndrome, Uroporphyrinogen HI cosyn Werner Syndrome, Wernicke's (C) I Syndrome, Wernicke's thase, Urticaria pigmentosa, Usher Syndrome, Usher Type I. aphasia, Wernicke-Korsakoff Syndrome, West Syndrome, Usher Type II, Usher Type III, Usher Type IV. Uterine Wet Beriberi, WHCR, Whipple's Disease, Whipple Disease, Synechiae, Uoporphyrinogen I-synthase, Uveitis, Uveomen Whistling face syndrome, Whistling Face-Windmill Vane ingitis Syndrome, V-CJD, VACTEL Association, VACTERL Hand Syndrome. White-Darier Disease, Whitnall-Norman Association, VACTERL Syndrome, Valgus Calcaneus, Syndrome, Whorled nevoid hypermelanosis, WHS, Valine Transaminase Deficiency, Valinemia, Valproic Acid, Wieacker Syndrome, Wieacher Syndrome, Wieacker-Wolff Valproate acid exposure, Valproic acid exposure, Valproic Syndrome, Wiedmann-Beckwith Syndrome, Wiedemann acid, Van Buren's Disease, Van der Hoeve-Habertsma Rautenstrauch Syndrome, Wildervanck Syndrome, Will Waardenburg-Ciauldi Syndrome, Variable Onset Immuno ebrand-Juergens Disease, Willi-Prader Syndrome, Williams globulin Deficiency Dysgammaglobulinemia, Variant Syndrome, Williams-Beuren Syndrome, Wilms Tumor, Creutzfeldt-Jakob Disease (V-CJD), Varicella Embryopathy, Wilms Tumor-Aniridia-Gonadoblastoma-Mental Retarda Variegate Porphyria, Vascular Birthmarks, Vascular Demen tion Syndrome, Wilms Tumor Aniridia Gonadoblastoma tia Binswanger's Type, Vascular Erectile Tumor, Vascular Mental Retardation, Wilms Tumor-Aniridia-Cienitourinary Hemophilia, Vascular Malformations, Vascular Malforma Anomalies-Mental Retardation Syndrome, Wilms Tumor tions of the Brain, Vasculitis, Vasomotor Ataxia, Vaso Pseudohermaphroditism-Nephropathy, Wilms Tumor and pressin-Resistant Diabetes Insipidus, Vasopressin-Sensitive Pseudohermaphroditism, Wilms Tumor-Pseuodohermaph Diabetes Insipidus, VATER Association, Vcf syndrome, roditism-Glomerulopathy, Wilson's Disease, Winchester Vcfs, Velocardiofacial Syndrome, VeloCardioFacial Syn Syndrome, Winchester-Grossman Syndrome, Wiskott-Ald drome, Venereal Arthritis, Venous Malformations, Ventricu rich Syndrome, Wiskott-Aldrich Type Immunodeficiency, lar Fibrillation, Ventricular Septal Defects, Congenital Ven Witkop Ectodermal Dysplasias, Witkop Tooth-Nail Syn tricular Defects, Ventricular Septal Defect, Ventricular drome. Wittmaack-Ekbom Syndrome, WM Syndrome, Tachycardia, Venual Malformations, VEOHD, Vermis Apla WMS, WNS, Wohlfart-Disease, Wohlfart-Kugelberg-We sia, Vermis Cerebellar Agenesis, Vernal Keratoconjunctivi lander Disease, Wolf Syndrome, Wolf-Hirschhom Chromo tis, Verruca, Vertebral Anal Tracheoesophageal Esophageal some Region (WHCR), Wolf-Hirschhorn Syndrome, Wolff US 2007/0021589 A1 Jan. 25, 2007 39

Parkinson-White Syndrome, Wolfram Syndrome, Wolman Childhood Soft Tissue Sarcoma, Chondrosarcoma, Chorio Disease (Lysomal Acid Lypase Deficiency), Woody Guth carcinoma, Chronic Lymphocytic Leukaemia, Chronic rie's Disease, WPW Syndrome, Writer's Cramp, WS, WSS, Myeloid Leukaemia, Colorectal Cancers, Cutaneous T-Cell WWS, Wyburn-Mason Syndrome, X-Linked Addison's Dis Lymphoma, Dermatofibrosarcoma-protuberans, Desmoplas ease, X-linked Adrenoleukodystrophy (X-ALD), X-linked tic-Small-Round-Cell-Tumour, Ductal Carcinoma, Endo Adult Onset Spinobulbar Muscular Atrophy, X-linked Adult crine Cancers, Endometrial Cancer, Ependymoma, Esoph Spinal Muscular Atrophy, X-Linked Agammaglobu ageal Cancer, Ewing's Sarcoma, Extra-Hepatic Bile Duct linemia with Growth Hormone Deficiency, X-Linked Agam Cancer, Eye Cancer, Eye: Melanoma, Retinoblastoma, Fal maglobulinemia, Lymphoproliferate X-Linked Syndrome, lopian Tube cancer, Fanconi Anaemia, Fibrosarcoma, Gall X-linked Cardiomyopathy and Neutropenia, X-Linked Cen Bladder Cancer, Gastric Cancer, Gastrointestinal Cancers, tronuclear myopathy, X-linked Copper Deficiency, X-linked Gastrointestinal-Carcinoid-Tumour, Genitourinary Cancers, Copper Malabsorption, X-Linked Dominant Conradi Germ Cell Tumours, Gestational-Trophoblastic-Disease, Hunermann Syndrome, X-Linked Dominant Inheritance Glioma, Gynaecological Cancers, Haematological Malig Agenesis of Corpus Callosum, X-Linked Dystonia-parkin nancies, Hairy Cell Leukaemia, Head and Neck Cancer, Sonism, X Linked Ichthyosis, X-Linked Infantile Agamma Hepatocellular Cancer, Hereditary Breast Cancer. Histiocy globulinemia, X-Linked Infantile Nectrotizing Encephal tosis, Hodgkin’s Disease, Human Papillomavirus, Hydatidi opathy, X-linked Juvenile Retinoschisis, X-linked form mole, Hypercalcemia, Hypopharynx Cancer, IntraCcu Lissencephaly, X-linked Lymphoproliferative Syndrome, lar Melanoma, Islet cell cancer, Kaposi's sarcoma, Kidney X-linked Mental Retardation-Clasped Thumb Syndrome, Cancer, Langerhans-Cell-Histiocytosis, Laryngeal Cancer, X-Linked Mental Retardation with Hypotonia, X-linked Leiomyosarcoma, Leukaemia, Li-Fraumeni Syndrome, Lip Mental Retardation and Macroorchidism, X-Linked Pro Cancer, Liposarcoma, Liver Cancer, Lung Cancer, Lymphe gressive Combined Variable Immunodeficiency, X-Linked dema, Lymphoma, Hodgkin’s Lymphoma, Non-Hodgkin’s Recessive Conradi-Hunermann Syndrome, X-Linked Lymphoma, Male Breast Cancer, Malignant-Rhabdoid-Tu Recessive Severe Combined Immunodeficiency, X-Linked mour-of-Kidney, Medulloblastoma, Melanoma, Merkel Cell Retinoschisis, X-linked Spondyloepiphyseal Dysplasia, Cancer, Mesothelioma, Metastatic Cancer, Mouth Cancer, Xanthine Oxidase Deficiency (Xanthinuria Deficiency, Multiple Endocrine Neoplasia, Mycosis Fungoides, Myelo Hereditary), Xanthinuria Deficiency, Hereditary (Xanthine dysplastic Syndromes, Myeloma, Myeloproliferative Disor Oxidase Deficiency), Xanthogranulomatosis Generalized, ders, Nasal Cancer, Nasopharyngeal Cancer, Nephroblas Xanthoma Tuberosum, Xeroderma Pigmentosum, Xero toma, Neuroblastoma, Neurofibromatosis, Nijmegen derma Pigmentosum Dominant Type, Xeroderma Pigmen Breakage Syndrome. Non-Melanoma Skin Cancer, Non tosum Type AI XPA Classical Form, Xeroderma Pigmen Small-Cell-Lung-Cancer-(NSCLC), Ocular Cancers, tosum Type B II XPB, Xeroderma Pigmentosum Type E V Oesophageal Cancer, Oral cavity Cancer, Oropharynx Can XPE, Xeroderma Pigmentosum Type C III XPC, Xeroderma cer, Osteosarcoma, Ostomy Ovarian Cancer, Pancreas Can Pigmentosum Type D IV XPD, Xeroderma Pigmentosum cer, Paranasal Cancer, Parathyroid Cancer, Parotid Gland Type F VI XPF, Xeroderma Pigmentosum Type G VII XPG, Cancer, Penile Cancer, Peripheral-Neuroectodermal-Tu Xeroderma Pigmentosum Variant Type XP-V. Xeroderma mours, Pituitary Cancer, Polycythemia Vera, Prostate Can Talipes-and Enamel Defect, Xerodermic Idiocy, cer, Rare-cancers-and-associated-disorders, Renal Cell Car Xerophthalmia, Xerotic Keratitis, XLP, XO Syndrome, XP, cinoma, Retinoblastoma, Rhabdomyosarcoma, Rothmund XX Male Syndrome, Sex Reversal, XXXXX Syndrome, Thomson Syndrome, Salivary Gland Cancer, Sarcoma, XXY Syndrome, XYY Syndrome, XYY Chromosome Pat Schwannoma, Sezary syndrome, Skin Cancer, Small Cell tern, Yellow Mutant Albinism, Yellow Nail Syndrome, YKL, Lung Cancer (SCLC), Small Intestine Cancer, Soft Tissue Young Female Arteritis, Yunis-Varon Syndrome, YY Syn Sarcoma, Spinal Cord Tumours, Squamous-Cell-Carci drome, Z-E Syndrome, Z- and -Protease Inhibitor Defi noma-(skin), Stomach Cancer, Synovial sarcoma, Testicular ciency, Zellweger Syndrome, Zellweger cerebro-hepato-re Cancer, Thymus Cancer, Thyroid Cancer, Transitional-Cell nal syndrome. ZES, Ziehen-Oppenheim Disease (Torsion Cancer-(bladder), Transitional-Cell-Cancer-(renal-pelvis-/- Dystonia), Zimmermann-Laband Syndrome, Zinc Defi ureter), Trophoblastic Cancer, Urethral Cancer, Urinary Sys ciency Congenital, Zinsser-Cole-Engman Syndrome, ZLS, tem Cancer, Uroplakins, Uterine sarcoma, Uterus Cancer, Zollinger-Ellison Syndrome. Vaginal Cancer, Vulva Cancer, Waldenstrom's-Macroglobu 0196. As used herein a "cancer refers to a group of linemia, Wilms Tumour. diseases and disorders that are characterized by uncontrolled 0.197 As used herein, a “brain disease or disorder” refers cellular growth (e.g. formation of tumor) without any dif to any disease or disorder of the brain which results in either ferentiation of those cells into specialized and different cells. impaired cognitive ability or abnormal pathology. Brain Cancers which can be treated using the methods of the diseases and disorders which can be treated using the present invention include, without being limited to, ABL1 methods of the present invention, include without being protooncogene, AIDS Related Cancers, Acoustic Neuroma, limited to, Acute Disseminated Encephalomyelitis, Arterio Acute Lymphocytic Leukaemia, Acute Myeloid Leukaemia, venous Malformations and Other Vascular Lesions of the Adenocystic carcinoma, Adrenocortical Cancer, Agnogenic Central Nervous System, Cavernous Malformation, Cere myeloid metaplasia, Alopecia, Alveolar soft-part sarcoma, bral Atrophy, Corticobasal Degeneration, Encephalopathy, Anal cancer, Angiosarcoma, Aplastic Anaemia, Astrocy Fahr's Syndrome, Kuru Moyamoya Disease, Neuronal toma, Ataxia-telangiectasia, Basal Cell Carcinoma (Skin), Migration Disorders, Progressive Multifocal Leukoencepha Bladder Cancer, Bone Cancers, Bowel cancer, Brain Stem lopathy, Pseudotumor Cerebri (Benign Intracranial Hyper ulioma, Brain and CNS Tumours, Breast Cancer, CNS tension), Transmissible Spongiform Encephalopathies, Wer tumours, Carcinoid Tumours, Cervical Cancer, Childhood nicke-Korsakoff Syndrome, Chordoma Craniopharyngioma Brain Tumours, Childhood Cancer, Childhood Leukaemia, Medulloblastoma Meningioma Pineal Tumors Pituitary US 2007/0021589 A1 Jan. 25, 2007 40

Adenoma Primitive Neuroectodermal Tumors Schwannoma various lymphoid tissues. Lymphocytes are divided into two Vascular Tumors, astrocytoma, glioblastomas, metastatic groups. T lymphocytes become the sensitized lymphocytes brain tumors, amyotrophic lateral Sclerosis (ALS), progres that directly attack (cellular immunity). B lymphocytes sive muscular atrophy, postpolio syndrome, Adrenoleukod produce antibodies (huumoral immunity) that attach to the yStrophy, Alexander Disease, Alpers Disease, Canavan Dis antigen and make phagocytes and body chemicals such as ease, Dementia with Lewy Bodies, Friedreich's Ataxia, complement proteins much more efficient in the destruction Spanish Friedreich's Ataxia, Hallervorden-Spatz Disease, of the antigen. Krabbe Disease, Leigh's Disease, Leukodystrophy, Monomelic Amyotrophy, Olivopontocerebellar Atrophy, 0201 Immune system disorders occur when the immune Opsoclonus Myoclonus, Paraneoplastic Syndromes, Peliza response is inappropriate, excessive, or lacking. Immuno eus-Merzbacher Disease, Progressive Multifocal Leukoen deficiency disorders occur when the immune system fails to cephalopathy, Progressive Supranuclear Palsy, Spanish fight tumors or invading Substances. This causes persistent Ramsay Hunt Syndrome Type II, Shy-Drager Syndrome, or recurrent infections, severe infections by organisms that Alzheimer's disease, amyotrophic lateral Sclerosis, aphasia, are normally mild, incomplete recovery from illness or poor attention deficit disorder with hyperactivity, back pain, response to treatment, and an increased incidence of cancer Bell’s palsy, brain cancer, brain diseases, carpal tunnel and other tumors. Opportunistic infections are widespread syndrome, cerebral palsy, Charcot-Marie-tooth disease, infections by microorganisms that are usually controllable. Creutzfeldt-Jakob disease, degenerative nerve diseases, 0202) This deficiency may affect any part of the immune dementia, dizziness and vertigo, dystonia, encephalitis, epi system. Most commonly, it involves decreased functioning lepsy, Guillain-Barre Syndrome, head and brain injuries, of T or B lymphocytes (or both), or deficient antibody headache and migraine, hydrocephalus, memory, meningi production. The causes include congenital/inherited defects tis, movement disorders, multiple Sclerosis, myasthenia and acquired immunodeficiency caused by a disease that gravis, neural tube defects, neurofibromatosis, neurologic diseases (general), pain, paralysis, Parkinson's disease, affects the immune system. peripheral nerve disorders, , pituitary disor 0203 Examples of congenital rimmunodeficiency disor ders, reflex sympathetic dystrophy, restless legs, Reye syn ders of antibody production (B lymphocyte abnormalities) drome, seizures, shingles (herpes Zoster), sleep disorders, include hypogammaglobulinemia (lack of one or more spe spina bifida, spinal cord diseases and injuries, spinal cord cific antibodies), which usually causes repeated mild respi injuries, stroke, thoracic outlet syndrome, tourette Syn ratory infections, and agammaglobulinemia (lack of all or drome, tremor, tuberous sclerosis, and West Nile virus. most antibody production), which results in frequent severe 0198 As used herein “inflammatory diseases and disor infections and is often fatal. Congenital disorders affecting ders' encompass those disease and disorders which result in the T lymphocytes may cause increased Susceptibility to a response of redness, Swelling, pain, and a feeling of heat fungi, resulting in repeated Candida (yeast) infections. in certain areas that is meant to protect tissues affected by Inherited combined immunodeficiency affects both T lym injury or disease. Inflammatory diseases which can be phocytes and B lymphocytes. It is often fatal within the first treated using the methods of the present invention, include, year of life because there is no resistance to disease or without being limited to, acne, angina, arthritis, aspiration infection. pneumonia, empyema, gastroenteritis, inflammation, intes 0204 People are said to be “immunosuppressed when tinal flu, NEC, necrotizing enterocolitis, pelvic inflamma they experience immunodeficiency that is caused by. medi tory disease, pharyngitis, PID, pleurisy, raw throat, redness, cations such as corticosteroids or other immunosuppressant rubor, Sore throat, stomach flu and urinary tract infections. medications. This is a desired part of treatment for disorders 0199 The treatment of diseases and disorders associated Such as autoimmune disorders. It is used after organ trans with immune function are also contemplated by the methods plantation to prevent transplant rejections. of the present invention. Immunosuppression is a disorder or condition where the immune response is reduced or absent. 0205 Immunosuppression is also a common side effect The immune system protects the body from potentially of chemotherapy to treat many types of cancer because the harmful Substances (antigens) such as microorganisms, tox chemotherapy often reduces the number of white blood cells ins, cancer cells, and blood or tissues from another person. available to fight infection. The immune response consists of general actions such as 0206 Acquired immunodeficiency may be a complica phagocytosis, where white blood cells engulf and destroy tion of diseases such as HIV infection and AIDS (acquired “foreign' material. It protects against specific antigens by immunodeficiency syndrome). Malnutrition, particularly producing antibodies (immunoglobulins), which are mol with lack of protein, can cause acquired immunodeficiency. ecules that attach to a specific antigen and make destruction Many cancers can cause immunodeficiency. of the antigen more efficient. It also protects against specific antigens by producing lymphocytes (a group of white blood 0207 Those who have had a splenectomy, or removal of cells) that become specialized (sensitized). The sensitized the spleen, face a higher risk of infection from certain lymphocytes “recognize’ the foreign Substance, and destroy encapsulated bacteria, Such as but not limited to Streptococ it. cus pneumoniae, that the spleen would normally help fight. 0200 Immunity is, in part, a product of lymphoid tissue 0208 Increasing age also reduces the effectiveness of the in the body that includes the thymus, lymph nodes, tonsils, immune system. Immune system tissues (particularly lym parts of the spleen and gastrointestinal tract, and bone phoid tissue Such as the thymus) shrink with aging. There is marrow. Lymphocytes (the specialized white blood cells that also reduced lymphocyte number and activity with increas provide acquired immunity) are produced or mature in ing age. US 2007/0021589 A1 Jan. 25, 2007

0209 The present invention, therefore, is directed in part, 0214. In yet another aspect, the present invention relates to the treatment of immunosuppressed individuals who are to the use of an agent capable of modulating the expression Suffering from, for example, without limitation, Ataxia of AGT-701, AGT-702, AGT-704, AGT-705, AGT-706, telangiectasia, DiGeorge syndrome, Chediak-Higashi Syn AGT-707, AGT-708, AGT-709 and/or AGT-710 or a deriva drome, Job syndrome, Leukocyte adhesion defects, Panhy tive, homolog or analog thereof in the manufacture of a pogammaglobulinemia, Bruton disease, Congenital medicament for the treatment of a condition characterized agammaglobulinemia, Selective deficiency of IgA, Com by healthy State, myopathy, obesity, anorexia, weight main bined immunodeficiency disease, Wiscott-Aldrich syn tenance, diabetes, disorders associated with mitochondrial drome, and Complement deficiencies. dysfunction, genetic disorders, cancer, heart disease, inflam 0210. As used herein, the term “infertility” refers to the mation, disorders associated with the immune system, infer inability to conceive an offspring. Disease and disorders tility, disease associated with the brain and/or metabolic associated with in infertility which can be treated using the energy levels. methods of the present invention include, without being 0215. In still yet another aspect, the present invention limited to, Varicocoele, Galactorrhoea-Hyperprolacti relates to the use of an agent capable of modulating the naemia, Cryptorchism (maldescended or ectopic testis), activity of AGT-701, AGT-702, AGT-704, AGT-705, AGT Gonadal dysgenesis, Young's syndrome, Klinefelter's Syn 706, AGT-707, AGT-708, AGT-709 and/or AGT-710 or a drome, Germinal cell aplasia, Haemochromatosis, Kallmann derivative, homolog, analog, chemical equivalent or syndrome, Myotonic dystrophy, 5-Alpha reductase defi mimetic thereof in the manufacture of a medicament for the ciency, Cystic fibrosis, Kartagener's syndrome, Incomplete treatment of a condition characterized by healthy state, androgen insensitivity, Kennedy's disease, Galactorrhoea myopathy, obesity, anorexia, weight maintenance, diabetes, Hyperprolactinaemia, Hypopituitarism, Epididymo-orchitis, disorders associated with mitochondrial dysfunction, Pituitary tumour, Amenorrhoea (Specific type of Female genetic disorders, cancer, heart disease, inflammation, dis ininfertility), Haemosiderosis, Hypokalaemic distal renal orders associated with the immune system, infertility, dis tubular acidosis, Idiopathic premature ovarian failure, Dys ease associated with the brain and/or metabolic energy pareunia, Coalactorrhoea-Hyperprolactinaemia, FSH recep levels. tor deficiency, Gonadal dysgenesis (female), Mullerian dys genesis, Trisomy X, Turner's syndrome, Kallmann 0216 A further aspect of the present invention relates to syndrome, Myotonic dystrophy, C21-hydroxylase defi the use of AGT-701, AGT-702, AGT-704, AGT-705, AGT ciency, Galactosaemia, Testicular feminization syndrome, 706, AGT-707, AGT-708, AGT-709 and/or AGT-710 or Malabsorption syndrome, Conn's syndrome, Cushing's Syn derivative, homolog or analog thereof or AGT-701, AGT drome, Diabetes mellitus type 2, Galactorrhoea-Hyperpro 702, AGT-704, AGT-705, AGT-706, AGT-707, AGT-708, lactinaemia, Hyperthyroidism, Hypopituitarism, Hypothy AGT-709 and/or AGT-710 or derivative, homolog, analog, roidism, Sheehan’s syndrome, Autoimmune adrenalitis, chemical equivalent or mimetic thereof in the manufacture Systemic lupus erythematosus, Adrenal cortex tumours, of a medicament for the treatment of a condition character Pituitary tumour, Prolactin secreting pituitary tumour, ized by obesity, anorexia, weight maintenance, diabetes Benign neoplastic conditions, Cushing's disease, Malignant and/or energy imbalance. neoplastic conditions, Ovarian cancer, Polycystic ovary Syn 0217 Still yet another aspect of the present invention drome and Pelvic inflammatory disease. relates to agents for use in modulating the expression of 0211 An agent includes proteinaceous or non-proteina AGT-701, AGT-702, AGT-704, AGT-705, AGT-706, AGT ceous molecules such as antibodies, natural products, chemi 707, AGT-708, AGT-709 and/or AGT-710 or a derivative, cal entities or nucleic acid molecules (including antisense hqmolog or analog thereof. molecules, sense molecules, ribozymes, ds-RNA molecules 0218. A further aspect relates to agents for use in modu or DNA-targeting molecules). lating AGT-701, AGT-702, AGT-704, AGT-705, AGT-706, 0212. An "effective amount’ means an amount necessary AGT-707, AGT-708, AGT-709 and/or AGT-710 activity or a at least partly to attain the desired immune response (e.g. derivative, homolog, analog, chemical equivalent or against AGT-701, AGT-702, AGT-704, AGT-705, AGT-706, mimetic thereof. AGT-707, AGT-708, AGT-709 or AGT-710) or to delay the 0219. Still another aspect of the present invention relates onset or inhibit progression or halt altogether the onset or to AGT-701, AGT-702, AGT-704, AGT-705, AGT-706, progression of a particular condition. AGT-707, AGT-708, AGT-709 and/or AGT-710 or deriva 0213. In accordance with these methods, AGT-701, AGT tive, homolog or analog thereof or AGT-701, AGT-702, 702, AGT-704, AGT-705, AGT-706, AGT-707, AGT-708, AGT-704, AGT-705, AGT-706, AGT-707, AGT-708, AGT AGT-709 and/or AGT-710 or AGT-701, AGT-702, AGT 709 and/or AGT-710 or derivative, homolog, analog, chemi 704, AGT-705, AGT-706, AGT-707, AGT-708, AGT-709 cal equivalent or mimetic thereof for use in treating a and/or AGT-710 or agents capable of modulating the expres condition characterized by one or more symptoms of healthy sion or activity of said molecules may be co-administered state, myopathy, obesity, anorexia, weight maintenance, with one or more other compounds or Other molecules. EBy diabetes, disorders associated with mitochondrial dysfunc “co-administered” is meant simultaneous administration in tion, genetic disorders, cancer, heart disease, inflammation, the same formulation or in two different formulations via the disorders associated with the immune system, infertility, same or different routes or sequential administration by the disease associated with the brain and/or metabolic energy same or different routes. By “sequential administration is levels. meant a time difference of from seconds, minutes, hours or 0220. In a related aspect of the present invention, the days between the administration of the two types of mol mammal undergoing treatment may be a human oran animal ecules. These molecules may be administered in any order. in need of therapeutic or prophylactic treatment. US 2007/0021589 A1 Jan. 25, 2007 42

0221) The terms “treating and “treatment as used agents, for example, parabens, chlorobutanol, phenol, Sorbic herein refer to a reduction in the severity and/or frequency acid, thirmerosal and the like. In many cases, it will be of symptoms associated with inter alia myopathy, obesity, preferable to include isotonic agents, for example, Sugars or anorexia, weight maintenance, diabetes, disorders associ sodium chloride. Prolonged absorption of the injectable ated with mitochondrial dysfunction, genetic disorders, can compositions can be brought about by the use in the com cer, heart disease, inflammation, disorders associated with positions of agents delaying absorption, for example, alu the immune system, infertility, disease associated with the minum monostearate and gelatin. brain and/or metabolic energy levels, including any condi tion associated with varying levels of selenoproteins, elimi 0228 Sterile injectable solutions are prepared by incor nation of symptoms and/or the underlying cause, prevention porating the active components in the required amount in the of the occurrence of symptoms of disease and/or the under appropriate solvent with optionally other ingredients, as lying cause and improvement or remediation of damage. required, followed by sterilization by, for example, filter sterilization, irradiation or other convenient means. In the 0222 “Treating a subject may involve prevention of the case of sterile powders for the preparation of sterile inject disorder or disease condition or adverse physiological event able solutions, the preferred methods of preparation are in a susceptible individual as well as treatment of a clinically vacuum drying and the freeze-drying technique which yield symptomatic individual by inhibiting a disease or disorder. a powder of the active ingredient plus any additional desired Generally, Such conditions involve, weakness (which may ingredient from previously sterile-filtered solution thereof. be intermittent), neuropathic pain, absent reflexes, gas trointestinal problem (gastroesophogeal reflux, delayed gas 0229 When AGT-701, AGT-702, AGT-704, AGT-705, tric emptying, constipation, pseudo-obstruction), fainting, AGT-706, AGT-707, AGT-708, AGT-709 and AGT-710 or absent or excessive Sweating resulting in temperature regu AGT-701, AGT-702, AGT-704, AGT-705, AGT-706, AGT lation problems weakness, hypotonia, cramping, muscle 707, AGT-708, AGT-709 and AGT-710 are suitably pro pain, proximal renal tubular wasting resulting in loss of tected, they may be orally administered, for example, with protein, magnesium, phosphorous, calcium and other elec an inert diluent or with an assimilable edible carrer, or it may trolytes, cardiac conduction defects (heart blocks) and car be enclosed in hard or soft shell gelatin capsule, or it may be dio myopathy, hypoglycaemia (low blood Sugar) and liver compressed into tablets, or it may be incorporated directly failure, visual loss and blindness, hearing loss and deafness, with the food of the diet. For oral therapeutic administration, diabetes and exocrine pancreatic failure (inability to make the active compound may be incorporated with excipients digestive enzymes), mitochondrial dysfunction, including and used in the form of ingestible tablets, buccal tablets, failure to gain weight, short statue, fatigue and respiratory troches, capsules, elixirs, Suspensions, syrups, wafers, and problems. the like. Such compositions and preparations should contain at least 1% by weight of active compound. The percentage 0223) Accordingly, the present invention contemplates in of the compositions and preparations may, of course, be one embodiment a composition comprising a modulator of varied and may conveniently be between about 5 to about AGT-701, AGT-702, AGT-704, AGT-705, AGT-706, AGT 80% of the weight of the unit. The amount of active 707, AGT-708, AGT709 and AGT-710 expression or AGT compound in Such therapeutically useful compositions is 701, AGT-702, AGT-704, AGT-705, AGT-706, AGT-707, such that a suitable dosage will be obtained. Preferred AGT-708, AGT-709 and AGT-710 activity and one or more compositions or preparations according to the present inven pharmaceutically acceptable carriers and/or diluents. In tion are prepared so that an oral dosage unit form contains another embodiment, the composition comprises AGT-701, between about 0.1 ug and 2000 mg of active compound. AGT-702, AGT-704, AGT-705, AGT-706, AGT-707, AGT 708, AGT-709 and AGT-710 or a derivative, homolog, 0230. The tablets, troches, pills, capsules and the like analog or mimetic thereof and one or more pharmaceutically may also contain the following: A binder Such as gum acceptable carriers and/or diluents. The compositions may tragacanth, acacia, corn starch or gelatin; excipients such as also comprise leptin or modulations of leptin activity or ob dicalcium phosphate; a disintegrating agent such as corn expression. starch, potato starch, alginic acid and the like; a lubricant 0224 For brevity, all such components of such a com Such as magnesium Stearate; and a Sweetening agent such a Sucrose, lactose or saccharin may be added or a flavouring position are referred to as “active components’. agent such as peppermint, oil of wintergreen, or cherry 0225. The compositions of active components in a form flavouring. When the dosage unit form is a capsule, it may Suitable for injectable use include sterile aqueous solutions contain, in addition to materials of the above type, a liquid (where water soluble) and sterile powders for the extempo carrier. Various other materials may be present as coatings or raneous preparation of sterile injectable solutions. In all to otherwise modify the physical form of the dosage unit. cases, the form must be sterile and must.be fluid to the extent For instance, tablets, pills, or capsules may be coated with that easy syringability exists. It must be stable under the shellac, Sugar or both. A syrup or elixir may contain the conditions of manufacture and storage and must be pre active compound, Sucrose as a Sweetening agent, methyl and served against the contaminating action of microorganisms propylparabens as preservatives, a dye and flavouring Such Such as bacteria and fungi. as cherry or orange flavour. Of course, any material used in 0226. The carrier can be a solvent or other medium preparing any dosage unit form should be pharmaceutically containing, for example, water, ethanol, polyol (for example, pure and Substantially non-toxic in the amounts employed. glycerol, propylene glycol and liquid polyethylene glycol, In addition, the active compound may be incorporated into and the like), suitable mixtures thereof, and vegetable oils. Sustained-release preparations and formulations. 0227. The preventions of the action of microorganisms 0231 Pharmaceutically acceptable carriers and/or dilu can be brought about by various antibacterial and antifungal ents include any and all solvents, dispersion media, coatings, US 2007/0021589 A1 Jan. 25, 2007

antibacterial and antifungal agents, isotonic and absorption 707, AGT-708, AGT-709 and AGT-710 are proteins. Such delaying agents and the like. The use of Such media and antibodies may be monoclonal or polyclonal and may be agents for pharmaceutical active Substances is well known in selected from naturally occurring antibodies to AGT-701, the art. Except insofar as any conventional media or agent is AGT-702, AGT-704, AGT-705, AGT-706, AGT-707, AGT incompatible with the active ingredient, use thereof in the 708, AGT-709 and AGT-710 or may be specifically raised to therapeutic compositions is contemplated. Supplementary AGT-701, AGT-702, AGT-704, AGT-705, AGT-706, AGT active ingredients can also be incorporated into the compo 707, AGT-708, AGT709 and AGT-710 or derivatives or sitions. homologs thereof. In the case of the latter, AGT-701, AGT 0232. It is especially advantageous to formulate 702, AGT-704, AGT-705, AGT-706, AGT-707, AGT-708, parenteral compositions in dosage unit form for ease of AGT-709 and AGT-710 or their derivatives or homologs administration and uniformity of dosage. Dosage unit form may first need to be associated with a carrier molecule. The as used herein refers to physically discrete units Suited as antibodies and/or recombinant AGT-701, AGT-702, AGT unitary dosages for the mammalian Subjects to be treated; 704, AGT-705, AGT-706, AGT-707, AGT-708, AGT-709 each unit containing a predetermined quantity of active and AGT-710 or their derivatives of the present invention are material calculated to produce the desired therapeutic effect particularly useful as therapeutic or diagnostic agents. An in association with the required pharmaceutical carrier. The antibody “to a molecule includes an antibody specific for specification for the novel dosage unit forms of the invention said molecule. are dictated by and directly dependent on (a) the unique 0237 AGT-701, AGT-702, AGT-704, AGT-705, AGT characteristics of the active material and the particular 706, AGT-707, AGT-708, AGT-709 and AGT-710 and their therapeutic effect to be achieved, and (b) the limitations derivatives can be used to screen for naturally occurring inherent in the art of compounding Such an active material antibodies to AGT-701, AGT-702, AGT-704, AGT-705, for the treatment of disease in living Subjects having a AGT-706, AGT-707, AGT-708, AGT-709 and AGT-710 diseased condition in which bodily health is impaired as which may occur in certain autoimmune diseases. Alterna herein disclosed in detail. tively, specific antibodies can be used to screen for AGT 0233. The principal active component may be com 701, AGT-702, AGT-704, AGT-705, AGT-706, AGT-707, pounded for convenient and effective administration in AGT-708, AGT.709 and AGT-710. Techniques for such Sufficient amounts with a suitable pharmaceutically accept assays are well known in the art and include, for example, able carrier in dosage unit form. A unit dosage form can, for sandwich assays and ELISA. example, contain the principal active component in amounts 0238 Antibodies to AGT-701, AGT-702, AGT-704, ranging from 0.5 Lig to about 2000 mg. Expressed in AGT-705, AGT-706, AGT-707, AGT-708, AGT-709 and proportions, the active compound is generally present in AGT-710 of the present invention may be monoclonal or from about 0.5 g to about 2000 mg/ml of carrier. In the case polyclonal and may be selected from naturally occurring of compositions containing Supplementary active ingredi antibodies to the AGT-701, AGT-702, AGT-704, AGT-705, ents, the dosages are determined by reference to the usual AGT-706, AGT-707, AGT-708, AGT-709 and AGT-710 or dose and manner of administration of the said ingredients. may be specifically raised to these gene products. In the case 0234. In general terms, effective amounts of AGT-701, of the latter, the AGT-701, AGT-702, AGT-704, AGT-705, AGT-702, AGT-704, AGT-705, AGT-706, AGT-707, AGT AGT-706, AGT-707, AGT-708, AGT-709 and AGT-710 pro 708, AGT-709 and AGT-710 or AGT-701, AGT-702, AGT tein may need first to be associated with a carrier molecule. 704, AGT-705, AGT-706, AGT-707, AGT-708, AGT-709 Alternatively, fragments of antibodies may be used such as and AGT-710 will range from 0.01 ng/kg/body weight to Fab fragments. Furthermore, the present invention extends above 10,000 mg/kg/body weight. Alternative amounts to recombinant and synthetic antibodies and to antibody range from 0.1 ng/kg/body weight to above 1000 mg/kg/ hybrids. A “synthetic antibody' is considered herein to body weight. The active ingredients may be administered include fragments and hybrids of antibodies. The antibodies per minute, hour, day, week, month or year depending on the of this aspect of the present invention are particularly useful condition being treated. The route of administration may for immunotherapy and may also be used as a diagnostic tool vary and includes intravenous, intraperitoneal, Sub-cutane or as a means for purifying AGT-701, AGT-702, AGT-704, ous, intramuscular, intranasal, via Suppository, via infusion, AGT-705, AGT-706, AGT-707, AGT-708, AGT-709 and via drip, orally or via other convenient means. AGT710. 0235. The pharmaceutical composition may also com 0239 For example, specific antibodies can be used to prise genetic molecules such as a vector capable of trans screen for AGT-701, AGT-702, AGT-704, AGT-705, AGT fecting target cells where the vector carries a nucleic acid 706, AGT-707, AGT-708, AGT-709 and AGT-710 proteins. molecule capable of modulating AGT-701, AGT-702, AGT The latter would be important, for example, as a means for 704, AGT-705, AGT-706, AGT-707, AGT-708, AGT-709 screening for levels of AGT-701, AGT-702, AGT-704, AGT and AGT-710 expression or AGT-701, AGT-702, AGT-704, 705, AGT-706, AGT-707, AGT-708, AGT-709 and AGT-710 AGT-705, AGT-706, AGT-707, AGT-708, AGT-709 and in a cell extract or other biological fluid or purifying AGT-710 activity. The vector may, for example, be a viral AGT-701, AGT-702, AGT-704, AGT-705, AGT-706, AGT Vector. 707, AGT-708, AGT-709 and AGT-710 made by recombi nant means from culture Supernatant fluid. Techniques for 0236 Still another aspect of the present invention is the assays contemplated herein are known in the art and directed to antibodies to AGT-701, AGT-702, AGT-704, include, for example, Sandwich assays and ELISA. AGT-705, AGT-706, AGT-707, AGT-708, AGT-709 and AGT-710 and their derivatives and homologs insofar as 0240. It is within the scope of this invention to include AGT-701, AGT-702, AGT-704, AGT-705, AGT-706, AGT any second antibodies (monoclonal, polyclonal or fragments US 2007/0021589 A1 Jan. 25, 2007 44 of antibodies) directed to the first mentioned antibodies sandwich assay technique exist, and all are intended to be discussed above. Both the first and second antibodies may be encompassed by the present invention. Briefly, in a typical used in detection assays or a first antibody may be used with forward assay, an unlabelled antibody is immobilized on a a commercially available anti-immunoglobulin antibody. An solid substrate and the sample to be tested brought into antibody as contemplated herein includes any antibody contact with the bound molecule. After a suitable period of specific to any region of AGT-119, AGT-120, AGT-121, incubation, for a period of time sufficient to allow formation AGT-122, AGT-422, AGT-123 and AGT-504. of an antibody-AGT-701, AGT-702, AGT-704, AGT-705, 0241. Both polyclonal and monoclonal antibodies are AGT-706, AGT-707, AGT-708, AGT-709 and AGT-710 obtainable by immunization with the enzyme or protein and complex, a second antibody specific to the AGT-701, AGT either type is utilizable for immunoassays. The methods of 702, AGT-704, AGT-705, AGT-706, AGT-707, AGT-708, obtaining both types of sera are well known in the art. AGT-709 and AGT-710, labeled with a reporter molecule Polyclonal sera are less preferred but are relatively easily capable of producing a detectable signal, is then added and prepared by injection of a suitable laboratory animal with an incubated, allowing time sufficient for the formation of effective amount of AGT-119, AGT-120, AGT-121, AGT another complex of antibody-AGT-701, AGT-702, AGT 122, AGT-422, AGT-123 and AGT-504, or antigenic parts 704, AGT-705, AGT-706, AGT-707, AGT-708, AGT-709 thereof, collecting serum from the animal, and isolating and AGT-710-labeled antibody. Any unreacted material is specific Sera by any of the known immunoadsorbent tech washed away, and the presence of AGT-701, AGT-702, niques. Although antibodies produced by this method are AGT-704, AGT-705, AGT-706, AGT-707, AGT-708, AGT 709 and AGT-710 is determined by observation of a signal utilizable in virtually any type of immunoassay, they are produced by the reporter molecule. The results may either be generally less favoured because of the potential heteroge qualitative, by simple observation of the visible signal, or neity of the product. may be quantitated by comparing with a control sample 0242. The use of monoclonal antibodies in an immunoas containing known amounts of hapten. Variations on the say is particularly preferred because of the ability to produce forward assay include a simultaneous assay, in which both them in large quantities and the homogeneity of the product. sample and labelled antibody are added simultaneously to The preparation of hybridoma cell lines for monoclonal the bound antibody. These techniques are well known to antibody production derived by fusing an immortal cell line those skilled in the art, including any minor variations as and lymphocytes sensitized against the immunogenic prepa will be readily apparent. In accordance with the present ration can be done by techniques which are well known to invention, the sample is one which might contain AGT-701, those who are skilled in the art. (See, for example, Douillard AGT-702, AGT-704, AGT-705, AGT-706, AGT-707, AGT and Hoflinan, Basic Facts about Hybridomas, in Compen 708, AGT-709 and AGT-710 including cell extract, tissue dium of Immunology Vol. II, ed. by Schwartz, 1981; Kohler biopsy or possibly serum, saliva, mucosal Secretions, lymph, and Milstein, Nature 256: 495-499, 1975; Kohler and Mil tissue fluid and respiratory fluid. The sample is, therefore, stein, European Journal of Immunology 6: 511-519, 1976.) generally a biological sample comprising biological fluid but 0243 Another aspect of the present invention contem also extends to fermentation fluid and Supernatant fluid Such plates a method for detecting AGT-701, AGT-702, AGT-704, as from a cell culture. AGT-705, AGT-706, AGT-707, AGT-708, AGT-709 and 0247 The solid surface is typically glass or a polymer, AGT-710 or a derivative or homolog thereof in a biological the most commonly used polymers being cellulose, poly sample from a subject, said method comprising contacting acrylamide, nylon, polystyrene, polyvinyl chloride or said biological sample with an antibody specific for AGT polypropylene. The solid supports may be in the form of 701, AGT-702, AGT-704, AGT-705, AGT-706, AGT-707, tubes, beads, discs or microplates, or any other Surface AGT-708, AGT-709 and AGT-710 or their antigenic deriva Suitable for conducting an immunoassay. The binding pro tives or homologs for a time and under conditions Sufficient cesses are well-known in the art and generally consist of for a complex to form, and then detecting said complex. cross-linking covalently binding or physically adsorbing, the polymer-antibody complex to the solid surface which is then 0244. The presence of the complex is indicative of the washed in preparation for the test sample. An aliquot of the presence of AGT-701, AGT-702, AGT-704, AGT-705, AGT sample to be tested is then added to the solid phase complex 706, AGT-707, AGT-708, AGT-709 and AGT-710. This and incubated for a period of time sufficient (e.g. 2-40 assay may be quantitated or semi-quantitated to determine a minutes or overnight if more convenient) and under Suitable propensity to develop obesity or other conditions or to conditions (e.g. from room temperature to about 37°C.) to monitor a therapeutic regimen. allow binding of any subunit present in the antibody. Fol 0245. The presence of AGT-701, AGT-702, AGT-704, lowing the incubation period, the antibody subunit solid AGT-705, AGT-706, AGT-707, AGT-708, AGT-709 and phase is washed and dried and incubated with a second AGT-710 may be accomplished in a number of ways such as antibody specific for a portion of AGT-701, AGT-702, by Western blotting and ELISA procedures. A wide range of AGT-704, AGT-705, AGT-706, AGT-707, AGT-708, AGT immunoassay techniques are available as can be seen by 709 and AGT-710. The second antibody is linked to a reference to U.S. Pat. Nos. 4,016,043, 4,424,279 and 4,018, reporter molecule which is used to indicate the binding of 653. These, of course, include both single-site and two-site the second antibody to AGT-701, AGT-702, AGT-704, AGT or 'sandwich' assays of the non-competitive types, as well 705, AGT-706, AGT-707, AGT-708, AGT-709 and AGT as in the traditional competitive binding assays. These 710. assays also include direct binding of a labelled antibody to 0248. An alternative method involves immobilizing the a target. target molecules in the biological sample and then exposing 0246 Sandwich assays are among the most useful and the immobilized target to specific antibody which may or commonly used assays. A number of variations of the may not be labelled with a reporter molecule. Depending on US 2007/0021589 A1 Jan. 25, 2007

the amount of target and the strength of the reporter mol detect AGT-701, AGT-702, AGT-704, AGT-705, AGT-706, ecule signal, a bound target may be detectable by direct AGT-707, AGT-708, AGT-709 and AGT-710 or their deriva labelling with the antibody. Alternatively, a second labelled tives. antibody, specific to the first antibody is exposed to the target-first antibody complex to form a target-first antibody 0253) Real-time PCR is also particularly useful for assay second antibody tertiary complex. The complex is detected ing for particular genetic molecules. by the signal emitted by the reporter molecule. 0254 The present invention is further described by the following non-limiting Examples. 0249. By “reporter molecule' as used in the present specification, is meant a molecule which, by its chemical EXAMPLE 1. nature, provides an analytically identifiable signal which allows the detection of antigen-bound antibody. Detection Psammomys obesus may be either qualitative or quantitative. The most com monly used reporter molecules in this type of assay are 0255 In the following examples, Psammomys obesus rats either enzymes, fluorophores or radionuclide containing were used for differential expression studies under different molecules (i.e. radioisotopes) and chemiluminescent mol conditions. The rats are divided into three groups, based on ecules. metabolic phenotype, as follows: 0250 In the case of an enzyme immunoassay, an enzyme 0256 Group A animals: lean is conjugated to the second antibody, generally by means of 0257) Group B animals: obese, non-diabetic glutaraldehyde or periodate. As will be readily recognized, however, a wide variety of different conjugation techniques 0258 Group C animals: obese, diabetic. exist, which are readily available to the skilled artisan. Commonly used enzymes include horseradish peroxidase, EXAMPLE 2 glucose oxidase, B-galactosidase and alkaline phosphatase, amongst others. The substrates to be used with the specific Sequence of Psanimoiny's obesus AGT-701 enzymes are generally chosen for the production, upon 0259 AGT-701 was identified using microarray analysis hydrolysis by the corresponding enzyme, of a detectable of red gastrocnemius muscle in exercise trained and control colour change. Examples of Suitable enzymes include alka P obesus. line phosphatase and peroxidase. It is also possible to employ fluorogenic Substrates, which yield a fluorescent 0260 The nucleotide sequence is as follows: product rather than the chromogenic Substrates noted above. In all cases, the enzyme-labelled antibody is added to the SEQ ID NO: 1 first antibody hapten complex, allowed to bind, and then the GGACATCTTTTCAGCCATGAGGAGCTTTCTGGAAACTCGGAGTTGATACA excess reagent is washed away. A solution containing the appropriate Substrate is then added to the complex of anti GAAATATAGGAATATAATCACGCAGGCTCCTAACCTGGAGAACATTGAGC body-antigen-antibody. The substrate will react with the enzyme linked to the second antibody, giving a qualitative TGTACTGGAACAGCTACAACAACCGCCGAGACCTGAACTTCGAGCGAGGT visual signal, which may be further quantitated, usually GGTGAGATGACCCTCAAGTGCCCTGTGATGCTGGTGGTAGGAGACCAAGC spectrophotometrically, to give an indication of the amount of hapten which was present in the sample. A “reporter GCCTCATGAGGATGCCGTGGTGGAGTGTAACT CAAAACTGGACCCCACAC molecule' also extends to use of cell agglutination or AGACCTCGTTCCTCAAGATGGCTGATTCTGGAGGTCAGCCACAGCTGACC inhibition of agglutination Such as red blood cells on latex beads, and the like. CAGCCAGGCAAGCTGACTGAGGCTTTCAAGTACTTNCTGCAAGGCATGGG 0251 Alternately, fluorescent compounds, such as fluo CTACATGGCCTCCTCCTGCATGACTCGCCTATCGAGGTCTCGCACGGCAT rescein and rhodamine, may be chemically coupled to anti bodies without altering their binding capacity. When acti CTTTGACCAGCGCAGCATCCATTGAT vated by illumination with light of a particular wavelength, the fluorochrome-labelled antibody absorbs the light energy, EXAMPLE 3 inducing a state to excitability in the molecule, followed by emission of the light at a characteristic colour visually AGT-701 detectable with a light microscope. As in the EIA, the 0261 AGT-701 demonstrated sequence homology to fluorescent-labelled antibody is allowed to bind to the first N-myc downstream-regulated gene 2 (NDRG2) antibody-hapten complex. After washing off the unbound reagent, the remaining tertiary complex is then exposed to EXAMPLE 4 the light of the appropriate wavelength. The fluorescence observed indicates the presence of the hapten of interest. AGT-701 Gene Expression Immunofluorescence and EIA techniques are both very well established in the art and are particularly preferred for the 0262 NDRG2 is a cytosolic protein of 371 amino acids present method. However, other reporter molecules. Such as with a molecular mass of 40.7 kDa (Zhou et al., Genomics radioisotope, chemiluminescent or bioluminescent mol 73(1): 86-97, 2001) and is encoded by a 2.4 kb mRNA. By ecules, may also be employed. radiation hybrid analysis, Kalaydieva et al. (Am. J. Hum. Genet. 67(1): 47-58, 2000) mapped the NDRG2 gene to 0252) The present invention also contemplates genetic chromosome 14q11.2. No information currently exists on assays such as involving, for example, PCR analysis to the function of NDRG2. The human and mouse NDRG2 US 2007/0021589 A1 Jan. 25, 2007 46 proteins are 92% identical (Zhou et al., 2001). Rat NDRG2 0267 NDRG1, NDRG2 and NDRG3 are all expressed in was recently identified and has approximately 90% homol a wide variety of tissues. NDRG2 is most highly expressed ogy to the mouse and human protein (Boulkroun et al., J. in adult skeletal muscle, brain and heart (Zhou et al., 2001; Biol. Chem. 277(35): 31506-31515, 2002). Qu et al., 2002), and NDRG3 is most highly expressed in brain and testis (Zhou et al., 2001: Quet al., 2002). NDRG4 0263) NDRG2 is part of the NDRG family, which is specifically expressed in brain and heart (Zhou et al., includes NDRG1, NDRG3 and NDRG4. At the amino acid level, the four members share 53-65% identity (Kalaydjieva 2001: Qu et al., 2002). et al., 2000; Zhou et al., 2001). NDRG1 and NDRG3 belong 0268 Zhou et al., 2001 identified two forms of NDRG2, to one subfamily and NDRG2 and NDRG4 to another. The with and without a 14 amino acid insertion in the N-terminal N— and C-terminal regions are the most divergent regions region, located after arnino acid number 25. This insertion between the four NDRG proteins, however the C-terminal was also present in mouse Ndr2. They designated the form five aa residues, Met-Glu-Val-Ser-Cys-COOH SEQ ID with the insertion NDRG2 and the form without the inser NO:12 are conserved in all human and mouse proteins. tion NDRG2'". Rat NDRG2 has four isoforms (Boulkroun There are three tandem repeats of GTRSRSHTSE SEQ ID et al., 2002). They differ in their 5' UTR sequence, which are NO:13 in the C-terminal region of NDRG1 which are not either 87 or 50 nucleotides in length, and the presence or present in NDRG2, NDRG3 and NDRG4. absence of the 42 base pairs (14 amino acids) insertion in the coding sequence at the same site as in human and mouse. 0264 All members of the NDRG family are cytosolic The proteins are 357 or 371 amino acids in length. The proteins (Qu et al., Mol. Cell. Biochem. 229(1-2): 35-44. insertion corresponds to the inclusion of exon 3 of the 2002). Each of the four proteins contains an O/B hydrolase human DRG2 gene, Suggesting an alternative splicing event. fold which is common to a number of hydrolytic enzymes, Sequences highly homologous to the 2 rat NDRG2 5' UTR Suggesting that NDRG2 may have an enzymatic function were found on different exons on the human NDRG2 gene, (Boulkroun et al., 2002). Hydrolases are enzymes that indicating that they might correspond to alternative 5' catalyze the hydrolysis of various bonds, e.g. C-O, C-N, untranslated exons (Boulkroun et al., 2002). This genomic C C, phosphoric anhydride bonds, etc. Hydrolysis is the organization strongly suggests the presence of alternative rupture of one or more chemical bonds by reaction with, and promoters which could direct expression of NDRG2 in a involving the addition of the elements of water. tissue specific and developmentally regulated manner. 0265 NDRG1 was the first of the family identified and 0269 NDRG2 has 34% identity to Drosophila MESK2, has been shown to be involved in stress responses, hormone a component of the Ras pathway (Boulkroun et al., 2002). responses, cell growth, and differentiation (Zhou et al., 2001 Ras is an upstream regulator of phosphatidylinositol 3 and references therein). NDRG1 gene expression is up kinase, and it may be hypothesized that NDRG2 may affect regulated by many agents. Such as reducing agents, tunica skeletal muscle insulin signalling through that pathway. mycin, lysophosphatidylcholine, okadaic acid, calcium ionophore, DNA damaging agents, nickel compounds, for 0270 A Glucocorticoid Responsive Element (GRE) half Skolin, and androgens. The gene is also up-regulated during site (TGTTCT) is present in the human NDRG2 promoter cell differentiation, in response to hypoxia, and at certain (Boulkroun et al., 2002). However, the glucocorticoid dex stages of the cell cycle in a p53-dependent manner. Over amethasone did not alter NDRG2 expression in RCCD2 expression of NDRG1 in tumor cells decreases the prolif cells, a rat kidney cortical collecting duct cell line, while the eration rate, enhances differentiation, and Suppresses the glucocorticoid-regulated gene Sgk was induced. metastatic potency of the cancer cells. In contrast, NDRG1 0271 In conclusion, NDRG2 belongs to a family of is repressed by N-myc and c-myc and in many tumor cells. genes putatively involved in growth arrest and induction of A nonsense mutation in the NDRG1 gene is causative for cell differentiation, the Ras pathway, and the peripheral hereditary motor and sensory neuropathy-Lom (HMSNL), a nervous system. Although it has strong homology to severe peripheral neuropathy characterized by Schwann cell NDRG1, it is not under negative regulation by N-myc. dysfunction and progressive axonal loss in the peripheral NDRG2 is a cytosolic protein, probably with an enzymatic nervous system. This suggests that NDRG1 functions in the function. peripheral nervous system necessary for axonal Survival. EXAMPLE 5 0266. After the identification of NDRG1 in human and mouse, two other members of the family were then identified Red Gastrocnemius Muscle: Exercise Training in mouse, Ndr2 and Ndr3 (Okuda and Kondoh, Biochem. Biophys. Res. Commun. 266(1): 208-215, 1999). In contrast 0272 AGT-701 gene expression in skeletal muscle of P to NDRG1, Ndr2 and Ndr3 were not under negative regu obesus increased with exercise training (p<0.001), and was lation by N-myc. Their expression during mouse develop negatively correlated with blood glucose (R =0.2872, ment indicates that the three members of the family are p=0.015) and the change in blood glucose after training under distinct spatio-temporal regulations, implying that (R=0.2291, p=0.033). AGT-701 expression also correlated genes of the NDRG family probably have tissue-dependent positively with energy expenditure (R =0.416, p=0.003). allotments of the possibly related functions (Okuda and Kondoh, 1999). Using the novel mouse sequences of Ndr2 EXAMPLE 6 and Ndr3 to search the databases, Kalayd jieva et al., 2000 identified the homologous human genes, Red Gastrocnemiuis Muscle: Fasting (24 h) which they referred as NDRG2 and NDRG3. Zhou et al., 0273 AGT-701 expression was significantly lower in C 2001 cloned NDRG3 and NDRG4, studied the human fed P. obesus, compared to A fed animals (p=0.011) and NDRG gene family and further characterized NDRG4. significantly higher in B fasted P. obesus compared to A US 2007/0021589 A1 Jan. 25, 2007 47 fasted (p=0.04) and C fasted animals (p=0.03). AGT-701 0279 The nucleotide sequence is as follows: expression negatively correlated with body fat (R-0.1803, p=0.043), body weight (R=0.2672, p=0.012) and blood SEQ ID NO:3 glucose (R=0.1865, p=0.04) in the fed P. obesus. TGACATTTTCTTTCCACCCTTAGATAGCTGATATATACTAAACTTA

EXAMPLE 7 TACAGAAATGTCAGTACTTGAACAAATTCAAAACACATTGGTTTATTAAC TTTTGGCTCATGCATGGTTTATTAGGTTCAAATTATACCTGATTCACTA Sequence of Psammomys obesus AGT-792 TATTTACTTTTAAAATGTGTGGTTTCCTCATTTTAAAAGTAAAACTAAAC 0274 AGT-702 was identified using microarray analysis of red gastrocnemius muscle in exercise trained and control AGTGCTTTTGGAATTTCTAAGCTACTAATTGTTGATAGATACAGCCTGTG P. Obesus. TCTAGTAAAATAGTTTTGTGGGTGTGGGTTCTATCTTTCCATGAAAAAGT

0275. The nucleotide sequence is as follows: GGGAGGTGTAAGTTAGTTTGGTTAGTGCCTAATAGTTAAATTTATATAAA

ATAAGAATGAGCATTTGGTATCTGTATGAAAGGGCCCTAAATCAAAATGA

SEQ ID NO: 2 TTATCCATAATCAATCTTTATTCTTGTTTTATAAAAACCAAAGGGCACTC GCTGGTACCGGTCCGGAATTCCCGGGATATCGTCGACCCACGCGTCCGGT ATTGGTTAAGTGTGCTGAGATAGAAAAG GGTGGAGAAGATCGCTCCTGCCGTGGTTCACATTGAACTGTATCGCAAAC

TTCCTTTCTCGAAGAGGGAGGTGCCAGTGGCGAGTGGGTCCGGATTTATC EXAMPLE 11 GTGTCTGAGGATGGACTGATTGTGACCAATGCTCACGTGGTGACCAACAA

AAACAGGGTCAAGGTTGAGCTGAAGAATGGAGCAACCTATGAAGCTAAAA AGT-704 Sequence Homology

TCAAGGATGTGGATGAAAAGGCAGACATCGCACTTATCAAAATTGACCAC 0280 AGT-704 demonstrated sequence homology to Mus musculus RIKEN cDNA 1200009K13 gene CAGGGAAAGCTGCCAGTCTTGCTGCTGGGCCGCTCCTCAGAGCTTCGACC (1200009K13Rik), mRNA. There are no human matches with the P. obesus sequence. However when BLASTing the AGGAGAGTTTGTGGTCGCCATCGGAAGCCCCTTTTCCCTTCAAAACACAG mouse sequence NM 025814 against the NR database, it TCACCACTGGGATCGTCAGTACCACCCAGCGAGGCGGCAAAGAGCTGGGG matches strongly to Homo sapiens CGI-55 protein MRNA and Homo sapiens PAI-1 mRNA-binding protein (PAI C RBP1). These are the same gene with the LocusLink and Unigene cluster calling it PAI-RBP 1. EXAMPLE 8 EXAMPLE 12 AGT-702 Sequence Homology AGT-704 Gene Expression 0276 AGT-702 demonstrated sequence homology to 0281) PAI-RBP1 is a 387 amino acid protein (with addi Protease, serine 11 (PRSS11). tional six and/or 15 amino acids insert in Some variants) that plays a role in regulation of mRNA stability. Regulation of EXAMPLE 9 mRNA stability is an important component of the regulation of gene expression and is known to have a significant role in Gene Expression as Measured by SYBR Green normal physiology and development. Real Time PCR: Red Gastrocnemius Muscle; Exercise Training 0282. The PAI-RBP1 protein binds to an A-rich region in the 3' 134 nucleotides of the PAI-1 mRNA. This 134 0277 AGT-702 gene expression in skeletal muscle of P nucleotides region is able to confer cyclic nucleotide regu obesus increased after exercise training (p<0.001) and was lation of mRNA stability and is, therefore, called the CRS negatively correlated with body weight (R =0.4538, (cyclic nucleotide-responsive sequence) The PAI-1 CRS p=0.008) in exercise trained P. obesus. AGT-702 expression includes a 75 nucleotide U-rich region at its 5' end and a 24 was positively correlated with energy expenditure (R = nucleotides A-rich region at its 3' end. Mutation of the A-rich 0.2823, p=0.019), and negatively correlated with blood portion reduces binding by PAI-RBP1 and eliminates cyclic glucose (R =0.3903, p=0.006). and the training induced nucleotide regulation of mRNA decay. change in blood glucose (R=0.1987, p=0.007) in all P 0283 The amino acid sequence of PAI-RBP1 includes an obesus. RGG box at amino acid 343-359, as well as an Arg-rich (amino acid 126-137) and an RG-rich (amino acid 163-184) EXAMPLE 10 motif, which places it in the general category with RNA binding proteins, even though it does not have other RNA Sequence of AGT-704 Psammomys obesus binding motifs such as an RNA recognition motif (RRM) or K-homology (KH) domain. The potential protein kinase A 0278 AGT-704 was identified using microarray analysis phosphorylation site (RKES) at serine 74 is also important of red gastrocnemius muscle in exercise trained and control given that this protein could be regulated by cyclic nucle P obesus. otides. US 2007/0021589 A1 Jan. 25, 2007 48

0284 PAI-RBP1 includes blocks of sequence that are EXAMPLE 13 highly conserved in a number of metazoans including mam mals, birds, Drosophila and Arabidopsis. Thus, PAI-RBP1 Gene Expression as Measured by SYBR Green identifies a family of proteins with a previously unidentified Real Time PCR: Red Gastrecnemitis Muscle; domain that may define a new RNA-binding motif. Exercise Training 0285 PAI-RBP1 has four splice variants, from two alter 0290 AGT-704 gene expression in skeletal muscle of P native splice sites, in both human and rat. An insertion of six Obesus increased with exercise training (p<0.001). AGT amino acids after position 202 is found in some transcripts, 704 gene expression negatively correlated with blood glu and an insertion of 15 amino acids after amino acid 226 is cose (R=0.3903, p=0.006) and positively correlated with found in some, both with or without the six amino acid energy expenditure (R =0.4767, p=0.001) in P. obesus. insert. 0286 PAI-RBP1 mRNA is expressed in a wide variety of EXAMPLE 1.4 tissues suggesting that it has a more general biological role involving regulation of mRNA stability or processes requir Red Gastrocnemius Muscle; Fasting (24 hr) ing interaction with RNA. 0291. There were no differences in AGT-704 gene 0287 Plasmin is a broad spectrum protease. It is the expression between the fed or the fasted groups of P. obesus, major fibrinolytic enzyme in blood and also participates in although there was a trend towards decreased expression in a number of physiological and pathological processes C fed P. obesus compared to A fed (p=0.08). However, involving localized proteolysis. Plasminogen is converted to AGT-704 gene expression showed a significant negative plasmin by plasminogen activators (PAS), which are serine correlation with blood glucose in fed P. obesus (R-0.3059, proteases and hydrolyze one peptide bond of plasminogen. p=0.007) Plasminogen activator activity is regulated by plasminogen activator inhibitor 1 (PAI-1). It is the mRNA of PAI-1 that EXAMPLE 1.5 PAI-1-RBP1 binds to. PAI-1 expression is also regulated by growth factors, cytokines and hormones including agents Sequence of AGT-705 Psammomys obesus that regulate cAMP levels. 0292 AGT-705 was identified using microarray analysis 0288 PAI-1 is consistently elevated in obesity and type 2 of red gastrocnemius muscle in exercise trained and control diabetes (ertens and Van Gaal, Obes. Rev. 3(2): 85-101, P. obesus. 2002). There is a strong positive correlation between this elevated PAI-1 and the degree of hyperinsulinemia. Both 0293. The nucleotide sequence is as follows: modest and Substantial weight loss have been found to significantly reduce PAI-1 levels. Recently it has been demonstrated that the adipocyte itself is able to produce SEQ ID NO: 4 PAI-1. Only the abdominal fat, not femoral subcutaneous CGCAGATACTGCAGAGCTGACGCATTCTTTGCCTGGCATCTCAGCTTGCT fat, PAI-1 gene expression contributes to increases in plasma AGGTGTCTCATCTTCGCTCTGCGCTCGTGGCCTCCTCCAAGGCCTCCAGT PAI-1 in obesity (Mavri et al., Diabetologia 44(11): 2025 2031, 2001). Adipose tissue also produces several effector CTCCTTTAAGAAAACTCAAGACCTGGGAAGCTACGATGCGAGCTTGATGC molecules that can up regulate PAI-1. These molecules include transforming growth factor B, TNF C. angiotensin II CGCTACCCTAGCAGGCTATGGACTTCCTGAGGGTCCTCGGACTGTTGACA and interleukin 6. Insulin stimulates PAI-1 gene expression CCCATTCCGATCCGCATCCTTCCAAGCTGATAAGCCCGGGACCCTAGGGC but glucose transport and PAI-1 gene expression are medi ated by different insulin signaling pathways (Samad et al., GGGGTGCCCAGACTCATGTGTGACGCCTTGCAGTGAAACCCCATTCCCAG Mol. Med. 6(8): 680-692, 2000). The disturbances in the TGGGTTGCTTCTTGCTGGGCTTTGGCCCATTGAACCACGAAGGATG haemostatic and fibrinolytic systems in part explains why obese and type 2 diabetic patients are at risk for the ACGATGCTAGTTATGCAGCAGCCAACACACCTCCCCCCAACTCTCCGCTG development of cardiovascular diseases. Increased PAI-1 TCACTGGTGGGCCCCACTGTCCAGGAAGCAGGTGTCCGGAACTGACATCT levels in the blood vessel wall decreases local fibrinolysis which may elevate thrombus formation and the evolution of TGGAGCAGAGGGGCCATGAGAGGTGTGTGTATCCTGCCAGAAAGCAGCTG atherosclerotic plaques (Pandolfi et al., Arterioscler Thomb. Vasc. Biol. 21 (8): 1378-1382, 2001). Chronic inflammation GACCACGACGCTCCCAAGATGAACCCACTGTATACAGAGGCATCATGGGA has emerged as a new risk factor for the development of type GTTGTTATGTCAGGAGCATTCTAGACCCACGTGTACTTGAGCGTGGAAAG 2 diabetes. Elevated levels of acute-phase proteins and PAI-1 predict type 2 diabetes independent of insulin resis ACAGAAGANANGCGCAGAGACTGGGGCACTTGATCTGCTCACCATGATCG tance and other known risk factors for diabetes (Festa et al., CCTGCACGGGTCTCATCCAGTTCCTGCCTTAGGCTACAGTGGCGGTGTCC 51(4): 1131-1137, 2002). 0289. A 4G/5G polymorphism in the PAI-1 promoter is ACGGGCTTGCCATTCAACGTGCTCTCAGACCCAGATCGGGCTCACCACTG strongly linked to obesity, and a markedly increased risk for AGGAGAACCTTTTCACTTTGGTGGGTATGCAGAGGGAAGGGTCTCGACTC obesity is associated with the 4G allele in its homozygous form (Hofstedt et al., Diabetologia 45(4): 584-587, 2002). CAGAGACCTGGAGCCAAAGTTTGTTTTTTTTTATTACCAGTAATTTAT Regular exercise has been shown to be effective for con trolling elevated PAI-1 levels in subjects homozygous for TTATTTTTTTTATATTAGTTAGAGCCAAAGTTTAATACCATTCAAGC the 4G allele (Vaisanen et al., Thomb. Haemost. 82(3): TACTGCTGTCTGTCTGCTTAGAGCCACAGCATGCAATGTGGCACCAAGGC 1117-1120, 1999). US 2007/0021589 A1 Jan. 25, 2007 49

EXAMPLE 19 -continued

ATCCTTGTCCCACAGTTTCACACTGTGGGAACAGGCATCCTTGTTCTTA Sequence of AGT-706 Psammomys obesus

CAGATTAGCGCGAGGGAAACCAGAAATATTAAACACGCAGGGTTGTCTCT 0297 AGT-706 was identified using microarray analysis of red gastrocnemius muscle in exercise trained and control CCAAAGGGAGAGGCACATACCCTGTTTTCCTCCCGAAGGCTGGGAGCGGA P obesus. GGGTTTGAACCTGGCTACCTCTGGCAATCGTAGGCCAGCCTTA 0298 The nucleotide sequence is as follows: AGATGTAGCTGTCAGTCGGTAGTGGAGCCGGAGCCGTCAGTCAGTAGATT

GGGGTTGTGGCATGCGCCTTTAACTCCATTTAATTCCAGCACTCTAGTGG SEQ ID NO: 5 GTTGGGAAAGAATGAAGAAACAACCCGATGAATAGAAATGAAAAGCCTAA TTTGGTACAGCAGCAGCAGCAGCGGTTGCAGTGGCCCGGGGAAGTCCTGA GCCAAATGGATTTCTGTTGAGATGTTGGATGAAAACAAGTATCCACTGTT AGACCAGCTTTCATCCCAGCACTCAGGCAGCAAAGGCGGGTGGATTCTCT TACCAACTTGACGAAAAATCTCAACTGAGGTTTGGCTGTTAAAAAAAAAA GAGTTCGAGGCCGGCCTGGTCTACAGAGTGAGTCCAGNCNAGCCAGGGCT ATTCACGTGGCCTCTGTGCTTAATTGTCGTAAACCATTGTGACTGTTAC ACAACAGAGAAANCCTCTCTATTGAAAAATAAATAAATTATAAAAAAAAA TGCTCAAAGTATCGTACTGTTCATTAGTAACTACATCAGAATTGCACCGC AAGGTGTCATGTGTCCTGTGTACTTTACAAAGAATGTTGATGCTTAAGCT TGCTGTTGGAAAAGCCAATAAAGAAACCCCCAGACTGCTGCTCAGCAAAT TTTTTGTGCACNCAAGAAAATTGTTTAACTGGTGTCAGACTCCTGAAGTT GTTAATAAAGTGTGCGCACCGTAGGCCTGTCCACCCAGTCACCAAGCAGC TGAACCAGCACTTAGCCNGGCGTGGTGGCGCACGCCTGTAATCCCAGCCC GTCCCTTTGTCTGCGAGTGGCTGTGGGTGTGATTNACCACCTCAGAGGTG TCGGGAGGCAGAGGCAGGTGGATCTCTGAGTTAGAGGCCAGCCTGGTCTA CACAGCACCTGCTTGNGCCCTTAAGTGTGNGTCAGAAGACAAGCAGCTTC CAGAGTGAGTCCAGGACAGCCAGGATTACACAGAGAAACCCCGTCTCAAA. TCGGTAACCAACAACCTGCTTTTCGGAGCTCAGTGTTTAGGCTGTTTACT AATGTAAAATAAATTAAAATAAAGTTTGAACCAACAGTGTTTACTGAGTC GAATCANATATGTAACTCAGCACACATAAGCGAAGAGAGATTTTGGCTGC GTGTTGAAACAGATTACCTTTTTGCTTCCTTGATCATTATTCACGT ACTGGCAAGAGTGAACCAAATTTACTTCTATTTTTTAAAGGCAGATCATA GGTGTCAGCAGAGACCCCTCCAGCAGGTGGCCAACGTGAGAGTCTCAAGC TTTAAGCATATAAGTAATTTATGGATATAAATTGTTGGATATTTATTTTA CCGAGAAGGTAAGAATTTAAAAAAAAAAAAAAAA GTCTGAATATTGTTTTTAAATTATTACAGGTTCCTATGTCTTAC

EXAMPLE 16 TCTGGAATAACGATGCCATTAACCACATGGCCATATGTTTTGAAAGTTGG AGT-705 Sequence Homology GTGNAACAGAGGAAAAGTCATCCTTCTTGGTTCTTGACTCCCTTTCCTCA 0294 The full clone sequence of AGT-705 matches a ACTACATGATAAGTCTATCAATAAAGCATTTGACCTCAGCAGGGGCAGAA mouse mRNA clone BC030414 (not full length mRNA) but GCCTGNAAAGTTAGAAAACTCATTGACCACAGTAGACAATTGATTTCTTA no human sequences on the GenBank database. GAAATAAGAAGTGAGAAGCAGCTGCTGNGCTGAGCAGGGGATGTAAACCA.

EXAMPLE 17 AGTCCAGATGCACCAACGTGAAGAGGCTTNTAGCAAAAATATGTTTGCCT Gene Expression as Measured by SYBR Green CTCACCCCTGCACATGTTCTAGATGCTTAAAAACAGCCACATGGCCCCGC Real Time PCR: Red Gastrocnemius Muscle; GCGAGGACCTCGTAATGGTTGGGTTGGTTGTTAAAGGAGT Exercise Training CTCACAAGCGTACAAGTGCAGCACTGAAAGTGGCTGAGGCCCACAGTCCT 0295) AGT-705 expression was not different between the exercise trained and the control P. obesus, although there CAGCACCCAAGTCTNTTCCGCAGCACGCCAAGCTGGTGTTGTCCGGGTGN was a tendency for expression to increase with exercise training (p=0.35). GTATGTCTGGCTCAGGCCAAGCTGGGTTTGGTCCCGTTGTATATAT GTGCCCCAAGTGTTTTGGGGCANAGCTGACCCANGCTGGACACACTTCTT

EXAMPLE 1.8 TTNGNCTTCGAGTTTACTGGTTGATNCAGNTAAAAATAAATTAATTAATT Red Gastrocnemius Muscle; Fasting (24 hr) AAAGACTT 0296) In this study, there was no difference in AGT-705 expression between the fed P. obesus, however, there was a EXAMPLE 20 trend towards increased expression in the C fed P. obesus. AGT-705 expression was significantly higher in the B fasted AGT-706 Sequence Homology group when compared with the Afasted group (p=0.035) and the C fasted group (p=0.007) and gene expression was 0299 AGT-706 demonstrated sequence homology to negatively correlated with blood glucose in the fasted P Human hypothetical protein FLJ20069 and mouse Ahi-1 obesus (R=0.3701, p=0.027). (also called mouse 1700015F03). US 2007/0021589 A1 Jan. 25, 2007 50

EXAMPLE 21 mus, expression was highest in the muscles, testes and ovary, however, detectable levels of gene expression were AGT-706 Gene Expression seen in most tissues. 0300. The Ahi-1 locus was initially identified as a com 0307 Expression of AGT-706 in liver cDNA decreased mon helper provirus integration site in Abelson pre-B-cell after fasting for 24h (p=0.001, t test). A positive correlation lymphomas and shown to be closely linked to the c-myb between AGT-706 gene expression in the liver and plasma proto-oncogene. Proviral integration within the Ahi-1 region insulin concentration was observed (R=0.1236, p=0.026). has also been shown in thymomas of T cell origin. 0308. In mesenteric fat, AGT-706 gene expression was 0301 Jiang et al. (J. Virol. 76(16): 9046-9059, 2002) significantly elevated in obese animals (p=0.004). identified the murine gene (Ahi-1) targeted by these provirus insertional mutations. The Ahi-1 cDNA encodes a 1,047 0309 Positive correlations between AGT-706 gene amino-acid protein. The predicted Ahi-1 protein is a modular expression in mesenteric fat and body weight (R-0.13, protein that exhibits several features of a signaling molecule. p=0.01) and insulin (R-0.1761, p=0.004) were observed. It contains one SH3 motif and seven WD40 repeats. The 0310 AGT-706 gene expression was examined in L6 Ahi-1 gene is conserved in mammals and encodes two major muscle cells treated with increasing concentrations of glu RNA species of 5 and 4.2 kb and several other shorter cose for 24 h. When cells were incubated in 17.5, 25 or 35 splicing variants. The Ahi-1 gene is expressed in mouse mM glucose, AGT-706 gene expression was significantly embryos and in several organs of the mouse and rat, notably elevated compared with cells incubated in 5 mM glucose at high levels in the brain and testes. (p<0.04). 0302) The Ahi-1 proviral insertions were found at the 3' end of the gene, in an inverse transcriptional orientation, EXAMPLE 24 with most of them located around and downstream of the last exon, whereas another insertion was within intron 22. In Sequence of AGT-707 Psammomys obesus addition, another previously identified provirus insertion 0311 AGT-707 was identified using microarray analysis site, Mis-2, was found to map within the 16th intron of the of red gastrocnemius muscle in exercise trained and control Ahi-1 gene. In tumor cells harboring insertional mutations in P obesus. Ahi-1, truncated Ahi-1/viral fused transcripts were identi fied, including some splicing variants with deletion of the 0312 The nucleotide sequence is as follows: SH3 domain. 0303. In summary, Ahi-1 encodes a protein that exhibits SEQ ID NO: 6 several features of a signaling molecule and is targeted by GTNGAAGCNTAGGAGTTCGAGGATGCGCCCGATGTCGAGCCGCTGGAACC provirus insertion. Ahi-1 may play an important role in signal transduction in normal cells and may be involved in CACGCTTAGCAATATCATCGAGCAGCGCAGCCTTAAGTGGATCTTCGTCG tumor development, possibly in cooperation with other GGGGCAAGGGTGGCGTTGGTAAGACCACCTGCAGCTGCAGCCTGGCGGTC oncogenes (such as V-abl and c-myc) or with a tumor Suppressor gene Nfl). CAGCTGTCTAAGGGACGTGAGAGTGTTCTAATCATTTCCACAGACCCAGC TCACAACATCTCAGATGCATTTGACCAGAAGTTCTCCAAGGTGCCTACCA EXAMPLE 22 AGGTCAAAGGCTATGACAACCTCTTTGCTATGGAGATAGACCCGAGCCTG Gene Expression as Measured by SYBR Green Real Time PCR: Red Gastrocnemius Muscle; GGCGTGGCAGAGCTCCCTGATGAAGTTCTTCGAGGAAGACAACATGCTGA Exercise Training GCATGGGCAAGAAGATGATGCAGGAGGCCATGAGCGCCTT 0304 AGT-706 gene expression increased in skeletal muscle of P. obesus after exercise training (p=0.001). In addition, AGT-706 gene expression was negatively corre EXAMPLE 25 lated with blood glucose (R =0.3903, p=0.012) and posi tively correlated with insulin (R=0.2213, p=0.036) and AGT-707 Sequence Homology energy expenditure (R =0.4031, p=0.003) in P. obesus. 0313 AGT-707 demonstrated sequence ASNA1: Human homolog of bacterial arSA arsenite transporter, ATP-binding. EXAMPLE 23 EXAMPLE 26 Red Gastrocnemius Muscle; Fasting (24 hr) 0305. In this study, AGT-706 gene expression was sig AGT-707Gene Expression nificantly higher in the B fasted and C fasted groups, when 0314 ASNA1 is the human homolog of the bacterial arSA compared to the A fasted group (p<0.001 for both compari gene. In E. coli, ArSA ATPase is the catalytic component of Sons). AGT-706 gene expression was negatively correlated a multi-subunit oxyanion pump that is responsible for resis with blood glucose in fed P. obesus, (R-0.2228, p=0.003) tance to arsenicals and antimonials. The E. coli ars operon and positively correlated with insulin in fasted P. obesus contains two regulatory (arsR and arsD) and three structural (R=0.2469, p=0.026). genes (arSA, B and C). The arSA gene codes for an oxyanion 0306 AGT-706 gene expression tissue distribution was ATPase that associates with the protein encoded for by arsR, examined in Psammomys obesus. Relative to the hypothala the channel-forming transmembrane protein. Together, the US 2007/0021589 A1 Jan. 25, 2007 two proteins transport arsenite and antimonite out of the proteins, respectively (Bhattachaoee et al., Gene 272: 291 cells across the plasma membrane. 299, 2001). Northern blot analysis detected a 1.3-kb tran 0315 Human ASNA1 encodes a 332-amino acid Script in mouse at highest levels in kidney and testis, polypeptide having an N-terminal ATP-binding cassette moderate levels in brain, liver, lung, and skin, low levels in (ABC) domain and a C-terminal domain of unknown func heart, Small intestine, spleen, stomach, and thymus, and tion (Kurdi-Haidar et al., Genomics 36: 486-491, 1996). The negligible levels in skeletal muscle. Bhattachaijee et al., protein sequence is highly homologous throughout both 2001 mapped the mouse Asna 1 gene to the C3-D1 region of domains to hypothetical arSA proteins of C. elegans and chromosome 8, and determined that it consists of seven yeast. Southern blot analysis indicated the existence of two exons spanning over 7 kb. closely related ARSA genes in the human genome. The EXAMPLE 28 existence of a second human ARSA protein was further supported by Western blot analysis, which demonstrated that Gene Expression as Measured by SYBR Green anti-ARSA1 antibodies identify two proteins of 37 and 42 Real Time PCR: Red Gastrocnemius Muscle; kD. Kurdi-Haider et al., 1996 expressed ASNA1 and found Exercise Training that the resulting 37-kD protein had ATPase activity. 0321 AGT 707 showed increased expression in the red 0316 Northern blot analysis revealed that the ASNA1 gastrocnemius muscle of exercise trained P. obesus com gene is expressed in a variety of tissues, with highest pared to control group animals (p=0.037). There were no expression in the cardiac and skeletal muscle (Kurdi-Haider correlations between gene expression and other phenotypic et al., 1996). Immunohistochemical analysis of normal variables. human tissues detected ASNA1 only in the epithelial cells of the liver, kidney, and stomach wall, in the adrenal medulla, EXAMPLE 29 in the islet cells of the pancreas, in the red pulp of the spleen, and in cardiac and skeletal muscle (Kurdi-Haidar et al., J. Red Gastrocnemius Muscle; Fasting (24 hr) Histochem. Cytochem. 46: 1243-1248, 1998d). In skeletal muscle the fibers were strongly positive. Interestingly, 0322 There were no differences in AGT-707 gene ASNA1 levels were markedly increased in breast fibroad expression between the fed groups or the fasted groups, enomas and carcinomas. although there was a trend for increased expression in group A compared to group B and C P obesus in the fed state 0317 ASNA1 shows a cytoplasmic, perinuclear, and (p=0.075 and p=0.055, respectively). AGT-707 gene expres nucleolar distribution (Kurdi-Haidar et al., J. Biol. Chem. sion was negatively correlated with body weight in the fed 273: 22173-22176, 1998a; Kurdi-Haidar et al., J. Cell. P. obesus (R=0.2267, p=0.026). Biochem. 71: 1-10, 1998b). Since the nuclear membrane and the nucleolus were enriched for ASNA1, with no detectable EXAMPLE 30 protein in the nucleoplasm, Suggests that the nuclear ASNA1 is bound and does not diffuse freely. The cytoplasmic Sequence of AGT-708 Psanmmomys obesus ASNA1 is soluble. The ASNA1 at the nuclear membrane was associated with invaginations into the nucleus in inter 0323 AGT-708 was identified using microarray analysis phase cells. These results and the fact that it is not found in of red gastrocnemius muscle in exercise trained and control the plasma membrane Suggest that ASNA1 is a paralog P obesus. rather than an ortholog of ArSA and that it probably plays a 0324. The nucleotide sequence is as follows: different role in human cells than does the Ars.A protein in bacteria. In human cells it appears to play a role in the nucleocytoplasmic transport of a nucleolar component. SEQ ID NO: 7 AAAATTTTACAAATGAGTGTGAATTGCATTCTGATATAATAATTATCACC 0318 Kurdi-Haider et al., 1998a characterized purified recombinant ASNA1. They determined that the ATPase CCACCACACTTTTACTGACACTGTTGATGGCCTATGCTGGTTTTCACA activity increases in the presence of sodium arsenite (but not antimonite) and that Vmax rather than ATP affinity is CACAATTCTTGTATGGAAAAATTTCTGTGGCCTGTGTAACCCCTCTGGTC enhanced. Human ASNA1 is an arsenite-stimulated rather AGTATTATGAAACCAACTATCTTTGGTGATAAATAAGGTTCCGGTAAGAT than an arsenite-dependent ATPase, and has significant basal ATPase activity even in the absence of oxyanions. Kurdi GCCCAGGGTTCATGAGTATGGCACAAATAACAGAGGACAGGAGGCCTTCA Haider et al., 1998a found that the active species is likely a CGACGAAGGAGCCCGTAAGTGGCCTGGAGGGCACAGATGCAGTTCCAGGT dimer or tetramer. CAAGAAAAGAGCAGCTTTTTCAACAGGCAGTCTGTGGGTATGATGGGAAC 0319 Kurdi-Haidar et al., Somat. Cell Molec. Genet. 24: 307-311, 1998c mapped the ASNA1 gene to chromosome TCAGCCTGTCTCTGTAGTTATGGACAGCGTGGCAGGTGACTGTGCCCACA 19q13.3 and determined that it contains four exons and spans 6 kb. CTTCCTATACAGGCTTTTTTTTTACTGACTGGAAGTACGTGAACTCA CTTAGTCCCCAACTGGACGTTTTCTGGAAAAACAAAGCAAATGTTAAAGT EXAMPLE 27 ATGTCTTTCTGGATATAGGCCAGNAGNAAATACATTAAGAATGAGAGGCC

Mouse ASNA1 Gene TTGCTTTGATCTCAGCCATTGGAGGCTAGAAAAAAATTGAAAGGAACCTT 0320 Mouse Asnal encodes a 348-amino acid protein CCTGTTGATAGACTCAAAGCCGTGAACAGAAGCCTCTTGGCCTGTTTCAG sharing 27% and 99% identity with the E. coli and human US 2007/0021589 A1 Jan. 25, 2007 52

kinase. Protein extracts inhibited both the C. (601639) and B -continued (176892) isoforms of the protein kinase catalytic subunit ACAATCTCTGGTAATCTACTGACAATATCCAACAGTTTCGATGTCCTTGT with equal efficacy. Using a transcriptional activation sys tem, Olsen and Uhler, 1991 demonstrated that elimination of TTAACTACCCTGGTAGCTTTCTTGTGGATTGAAGTTCATTTTTAAAGCT a conserved alternative translation start site in PKI increased

GTGGAATTTCAAACTGAATTCACGTGCATTTTGTAAAAGTTCAGAACCAG the inhibitory activity of the PKI expression vector.

GCTGAGTCTGTGTGGCAGGTTTTTTTCACCGCGTGATATACTATTACAA EXAMPLE 34 ATGCATGTGGTGCCATGCTTGTCTTCAAATATATAAGTAGTGCTAAATGG Gene Expression as Measured by SYBR Green ATAAGTCATATGGAGCTTTTGATTTAG Real Time PCR: Red Gastrocnemius Muscle; Exercise Training EXAMPLE 31 0329 AGT-708 gene expression in skeletal muscle of P AGT-708 Sequence Homology obesus was negatively correlated with activity (R-0.3543, p=0.006) and the change in carbohydrate oxidation after 0325 AGT-708 demonstrated sequence homology to exercise training (R-0.368, p=0.01), and was positively Protein kinase inhibitor C. (PKIO). correlated with energy expenditure (R-0.5377, p<0.001) EXAMPLE 32 and the change in fat oxidation after exercise training (R=0.3987, p=0.007) when all animals were analyzed AGT-708 Gene Expression together. AGT-708 gene expression positively correlated 0326 cAMP-dependent protein kinases co-ordinate cel with food intake (R-0.2996, p=0.043) and the change in fat lular responses to hormones and neurotransmitters by alter oxidation (R =0.3452, p=0.047) and negatively correlated ing processes such as cell division, membrane permeability with the change in carbohydrate oxidation (R =0,395, and transcription. Most of the effects of cAMP in the p=0.021) in the exercise trained P. obesus. eukaryotic cell are mediated through the phosphorylation of target proteins on serine or threonine residues by the cAMP EXAMPLE 35 dependent protein kinase (EC 2.7.1.37). The inactive cAMP dependent protein kinase is a tetramer composed of two regulatory and two catalytic subunits. The cooperative bind Red Gaswocnemius Muscle; Fasting (24 hr) ing of four molecules of cAMP dissociates the enzyme in a 0330 AGT-708 gene expression was significantly higher regulatory subunit dimer and two free active catalytic Sub units. In the human, four different regulatory Subunits in the B fasted and C fasted groups when compared to the (PRKAR1A, PRKAR1B, PRKAR2A, and PRKAR2B) and A fasted group (p<0.013 for both groups). AGT-708 gene three catalytic subunits (PRKACA, PRKACB and expression positively correlated with blood glucose in fasted PRKACG) have been identified. P. obesus (R=0.2512, p=0.021). 0327 Members of the cAMP-dependent protein kinase inhibitor family are specific and extremely potent competi EXAMPLE 36 tive inhibitors of cAMP-dependent protein kinase activity. These proteins interact with the catalytic subunit of the Sequence of AGT-709 Psammomys obesus enzyme after the cAMP-induced dissociation of its regula tory chains. The inhibitory site contains regions very similar 0331 AGT-709 was identified using microarray analysis to the hinge regions (sites that directly interact with the of red gastrocnemius muscle in exercise trained and control enzyme active site) and “pseudosubstrate site' of the regu P obesus. latory chains; but unlike these chains, PKI does not contain cAMP-binding sites. The arginine residues within the inhibi 0332 The nucleotide sequence is as follows: tory site are essential for inhibition and recognition of the enzyme active site. SEQ ID NO: 8 TGAGATAGCTACTCCATAAGCCTCTGAAGAGCAATAGCTAATTTATTATT EXAMPLE 33 ACTGTAATTNTTTTAAAGGCTTTAAAGTGCCTCGGGGGTTCCTTGAAACT Cloning AATTTTCTACTTCTGGGATTCCCTGGATTCTTTATAAGAGATGGTGACAT 0328. Using the mouse protein kinase inhibitor-alpha to screen a human neuroblastoma cell line cDNA library, Olsen GACTAGGGAAATTCTTTTTTTAGTAGAAAATTGTCCCTTCAATACTTTT and Uhler (Molec. Endocr: 5: 1246-1256, 1991) isolated CTCTTACTGGCATTGAATTATCACAGAGACAGAAAATTGGTAATTTTTTT clones encoding human PKIA. The deduced 75-amino acid PKIA protein shares 100% and 97% sequence identity with AATTTCTAACTCTCCCAGAAAACCCTCTTGCCTAGTATTTATTGATGT the rabbit and mouse homologs, respectively. Northern blot analysis detected major 4-kb and minor 2-kb PKIA tran GCTTTAACCATGGGAGGAGGGGTGGGGGGGGAACTCATTCAAGCTGCCAG Scripts in skeletal muscle. Using kinase assays with trans TATTTTGATCTACAACCTGTAGCA fected COS cells, Olsen and Uhler, 1991 verified that the PKIA cDNA produces a heat-stable inhibitor of protein US 2007/0021589 A1 Jan. 25, 2007

EXAMPLE 37 EXAMPLE 41 AGT-799 Sequence Homology AGT-710 Sequence Homology 0333 AGT-709 demonstrated sequence homology to 0338 AGT-710 demonstrated sequence homology to Ste Human KIAAO663 rol carrier protein 2 (SCP2) EXAMPLE 42 EXAMPLE 38 AGT-710 Gene Expression Gene Expression as Measured by SYBR Green 0339 Sterol carrier protein 2 (SCP-2, SCP2) is also Real Time PCR: Red Gastrocnemius Muscle; known as Nonspecific lipid-transfer protein, mitochondrial Exercise Training precursor (NSL-TP) and Sterol carrier protein X (SCP-X, SCPX) (SCP2 Genecard record, Genecards Website, Weiz 0334 There was no difference in AGT-709 gene expres mann Instsitute of Science: Human SCP-2 (NLTP HU sion in exercise trained animals when compared to controls. MAN) record froM SWISS-PROT database, ExPasy Web A significant positive correlation between AGT-709 gene site). The SCP-2 gene is a fusion gene that has two initiation expression and body weight (R-0.37, p=0.004) and energy sites. The gene encodes two proteins: SCP-2 and SCP-X. expenditure (R=0.5377, p=0.008) was found when all ani Both proteins share the same C-terminal 13 kDa (123 aa) mals were analyzed together. AGT-709 expression in exer sequence. The SCP-2 transcript encodes a 15 kDa (143 cise trained animals showed a positive association with body amino acid) pro-SCP-2 protein which is post-translationally weight (R-0.4538, p=0.045), and the change in glucose cleaved to form the mature 13 kDa SCP-2 protein. The (R=0.3198, p=0.035) and in body weight (R=0.3244, longer isoform, SCP-X, is translated into a 58 kDa (547 p=0.033) after exercise training amino acid) protein and is partially cleaved to form two proteins—the 13 kDa SCP-2 and a 45 kDa (404 amino acid) protein (Gallegos et al., Prog. Lipid. Res. 40(6): 498-563, EXAMPLE 39 2001). The latter is a 3-ketoacyl-CoA-thiolase specific for branched chain acyl CoAs (Stolowich et al., Cell Mol. Life Red Gastrocnemius Muscle; Fasting (24 hr) Sci. 59(2): 193-212, 2002). In most tissues however, the 0335 AGT-709 expression was significantly lower in the majority of the 58 kDa protein remains intact (Stolowich et C fed P. obesus than the A fed P. obesus(p=0.049), although al., 2002). there were no differences in gene expression between the 0340. The 13 kDa SCP-2 binds a number of different fasted groups. AGT-709 expression was negatively corre ligands such as fatty acids, fatty acyl CoAs, cholesterol and phospholipids. It is thought that the 13 kDa SCP-2 facilitates lated with body weight (R-0.2158, p=0.039) and blood the intracellular transport of lipids such as cholesterol glucose (R=0.2495, p=0.026) in fed P. obesus. between membranes. SCP-2 has been shown to also interact with a number of other ligands, and other possible physi EXAMPLE 40 ological functions are being examined (Gallegos et al., 2001). Sequence of AGT-710 Psammomys obesus 0341 Related genes proteins that also contain the C-ter 0336 AGT-710 was identified using microarray analysis minal SCP-2 domain are: DHB4 HUMAN: 17 B-hydrgxys teroid dehydrogenase IV (DBH4 record from Pfam database of red gastrocnemius muscle in exercise trained and control of protein families Website, Sanger Centre; Gallegos et al., P obesus. 2001) (the C-terminal SCP-2 domain is known to be 0337 The nucleotide sequence is as follows: required for peroxisomal import of this protein) and UNC 24 protein from C. elegans (this protein consists of an N-terminal SPFH (or band 7) domain and a SCP-2-like SEQ ID NO: 9 C-terminal domain. The human homologue of this protein is CCCACGCAGTCCGGGTGGCTCTGCAGCACAATTTAGGCCTTGGAGGAGCT stomatin-like protein (hSLP). Its function is unknown (Gal legos et al., 2001; Barnes et al., J. Neurochem. 67(1): 46-57, GTGGTTGTCACCCTCTACAANATGGGCTTCCCCGAAGCGGNCAGCTCCTT 1996). CAGAACACACCANATTTCGGCTGCTCCCACCAGCTCTGCAAGGGATGGAT EXAMPLE 43 TCAAGGCCAATCTTGTCTTTAAGGAGATCGAGAAGAAGCTTGAAGAGGAA

GGGGAACAGTTCGTGAAGAAGATCGGTGGGATTTTTGCCTTCAAAGTGAA Chromosomal Location and Gene Structure

GGACGGCCCTGGAGGCAAAGAAGCCACCTGGGTGGTGGATGTGAAGAATG 0342. The SCP-2 gene is located at chromosome 1 p32 (Vesa et al., Hum. Molec. Genet. 3: 341-346, 1994; SCP2 GCAAGGGATCCGTGCTTCCCAACTCAGATAAGAAGGCTGACTGCACAATC Genecard record, Genecards Website, Weizmann Institute of Science: Sterol Carrier Protein 2 record, OMIM Website). It ACCATGGCCGACTCCGACTTGCTGGCTCTGATGACTGNCAAAATGAACCC consists of 16 exons and 15 introns in humans, mice, rats and chickens (Ohba et al., Genomics 24: 370-274, 1994). The TC mouse homoldgue is found on chromosome 4 (Welch et al., Genome 7: 624–625, 1996). There are 2 promoter regions US 2007/0021589 A1 Jan. 25, 2007 54 that initiate at least 4 mRNA species (Stolowich et al., 2002). 48065, 2001) and SCP-X (Bun-ya et al., J. Biochem. Two alternatively polyadenylated mRNA transcripts (Tokyo) 123(2): 347-352, 1998; Ferdinandus.se et al., J. (mRNAs of 2.8 kB and 2.2 kb) encode the 58 kDa SCP-X Lipid. Res. 41(3): 336-342, 2000; Wanders et al., J. protein, and two alternatively polyadenylated transcripts Inherit. Metab. Dis. 21(3): 302-305, 1998) participate (mRNAs of 1.5 kb and 0.9 kb) encode the 15 kDa pro-SCP-2 in different aspects of bile acid synthesis. protein (Stolowich et al., 2002). Another study (Yamamoto et al., Proc. Natl. Acad. Sci. USA 88(2): 463-467, 1991) 0354 SCP-2 is believed to be involved in transport of identified a further two transcripts in the liver (1.8 kB and cholesterol from ER to bile (Ito et al., Gastroenterology 3.2 kb species) where the 1.8 kb isoform was most abundant. 110(5): 1619-1627, 1996). Little is known about the transcriptional regulation of the 0355 SCP-2 and possibly SCP-X and pro-SCP-2 are gene (Gallegos et al., 2001). believed to be involved in triacylglyceride formation (Seedorf et al., Genes Dev. 12(8): 1189-1201, 1998: EXAMPLE 44 Atshaves et al., J. Lipid Res. 40(4): 610-622, 1999; Murphy and Schroeder, Biochim. Biophys. Acta. Structural Features 1345(3): 283-292, 1997: Starodub et al., Am. J. Physiol. 0343. The secondary and tertiary structures for the 13 Cell Physiol. 279(4): C1259-1269, 2000). kDa molecule are available (Stolowich et al., 2002: Szyper 0356. SCP-2 and possible SCP-X and pro-SCP-2 are ski et al., FEBS Lett. 335(1): 18-26, 1993), however no believed to participate in peroxisomal fatty acid oxi structures are available for the 15 kDa, 45 kDa or 58 kDa dation (Seedorf et al., 1998; Schroeder et al., Biochem molecules. At the protein sequence level the SCP-X protein istry 34(37): 11919-11927, 1995; Ossendorp et al., consists of 3 domains (SCP-2 record from Pfam database of protein families Website, Sanger Center): Arch. Biochem. Biophys. 334(2): 251-260, 1996). 0357 SCP-2 is thought to facilitate cholesterol trans 0344) Thiolase N-terminal domain (residues 11-240). port to mitochondria and be involved in regulating 0345 Thiolase C-terminal domain (residues 245-402). steroidogenesis (Yamamoto et al., Proc. Natl. Acad. Sci. USA 88(2): 463-467, 1991; Yamamoto Hokkaido 0346 SCP-2 at the C-terminal of the protein (residues Igaku Zasshi 67: 839-848, 1992). 433-543). 0358. The 58 kDa SCP-X is one of three 3-ketoacyl 0347 The mature 13 kDa SCP-2 protein consists of only CoA thiolases found in peroxisomes. SCP-X is the SCP-2 domain. A tertiary structure is available for this believed to play an exclusive role in peroxisomal molecule (Stolowich et al., 2002). Functionally important branched chain fatty acid oxidation (Antonenkov et al., structural elements that have been identified by elucidation J. Biol. Chem. 272(41): 26023-26031, 1997: Antonen of the structure are: kov et al., Protein Expr: Purif 18(3):249-256, 2000; 0348 The N-terminal 32 residues forman amphipathic Wanderrs et al. Biochem. Biophys. Res. Commun. helix, one face of which is a membrane binding domain 236(3): 565-569, 1997) and in oxidation of the that binds to anionic phospholipids at membrane Sur branched side chain of cholesterol to form bile acids faces. (Fuchs et al., 2001: Bun-ya et al., 1998; Ferdinandusse 0349 The hydrophobic faces of the N-terminal amphi et al., 2000). pathic helices plus B-strands 4.5 and B-helix D form a EXAMPLE 46 ligand-binding cavity able to accommodate multiple types of lipids (fatty acids, acyl coAs, cholesterol, Scp2 Knockout Mice phospholipids, isoprenoids). 0359 scp2 null mice show a severe block at the level of 0350. The C-terminus is highly hydrophobic and it is thiolytic cleavage in pristanic acid B-oxidation and lack thought to form a hydrophobic cap that closes around normal peroxisomal degradation of the cholesterol side the ligand upon binding. chain in bile acid synthesis. The knockout mice show spontaneous peroxisome proliferation and increased mRNA EXAMPLE 45 levels of genes regulated by PPARC. The scp2 null pheno type is similar to that seen in acyl-CoA oxidase (ACO) null Putative Biochemical Function mice (Kannenberg et al., J. Biol. Chem. 274(50): 35455 0351 Gallegos et al., 2001 and Stolowich et al., 2002 35460, 1999). The scp2 null mice also have affected per have reviewed the various functions of SCP-2. In summary: oxisomal C-oxidation of phytanic acid (Atshaves et al., 1999). Whether these phenotypes are secondary affects of 0352 SCP-2 is believed to affect cholesterol synthe the gene knockout has yet to be clarified (Seedorf et al., sis—overexpression in mice of the rat SCP-2 gene by Biochim. Biopsies. Acta. 1486(1): 45-54, 2000). adenoviral infection increased liver cholesterol levels by 70% and decreased liver cholesterol synthesis by EXAMPLE 47 60% (Zanlungo et al., Gastroenterology 119(6): 1708 17-19, 2000). Tissue Distribution 0353 SCP-2 (Fuichs et al., Biochem. J. 336(1): 33-37, 0360. The human SCP2 gene was cloned from the liver 1998: Publielli et al., Biochem. J. 317(3): 681-687, (Yamamoto et al., 1991). The protein has been found most 1996; Kawata et al., Clin. Chim. Acta 197(3): 201-208, highly expressed in liver, intestine, adrenal and kidney 1991: Fuchs et al., J. Biol. Chem. 276(51): 48058 (Baum et al., J. Lipid. Res. 34(5): 729-739, 1993). It is also US 2007/0021589 A1 Jan. 25, 2007

expressed in lung, brain, testes, ovary and heart, fibroblasts, EXAMPLE 51 and placenta (Human SCP-2 (NLTP HUMAN) record from SWISS PROT database, ExPasy Website). EST data from Gene Expression as Measured by SYBR Green normal human tissues in Unigene indicate that the gene is Real Time PCR: Red Gastrocnemius Muscle; expressed in bone marrow, brain, heart, skeletal muscle, Exercise Training liver, pancreas, prostate, kidney, and lung (SCP2 Genecard 0366 AGT-710 gene expression in skeletal muscle of P record, Genecards Website, Weizmann Institute of Science). obesus increased with exercise training (p=0.016). Gene expression was positively correlated with energy expendi EXAMPLE 48 ture when all P obesus were analysed together (R =0.6508, p=0.001). Gene expression was negatively correlated with Cellular Localization blood glucose (R=0.3903, p=0.016) and activity (R= 0.3543, p=0.030) when all P. obesus were analyzed together. 0361) The identical C-termini of both SCP-2 and SCP-X Gene expression was positively correlated with fat oxidation contain an SKL peroxisomal targeting signal, however, as (R=0.3147, p=0.046) and the change in fat oxidation (R = much as half of the total SCP-2 is located outside the 0.3452, p=0.035) in exercise trained P. obesus. peroxisome. The SCP-2 N-terminal presequence in the pro SCP-2 protein strongly modulates intracellular targeting EXAMPLE 52 coded for by the C-terminal peroxisomal signal sequence (Gallegos et al., 2001; Stolowich et al., 2002). Other studies Red Gastrocnemius Muscle; Fasting (24 hr) indicate that mammalian SCP-2 is found in the cytoplasm or 0367 AGT-710 gene expression was significantly lower the mitochondria and that SCP-X is found in peroxisomes in C fed P. obesus when compared to A fed P. obesus (Baker et al., DNA Cell Biol. 10(9): 695-698, 1991: Interpro (p=0.021). AGT-710 gene expression was negatively corre database of proteins http://www.ebi.ac.uk/interpro/Ien lated with body weight (R=0.2267, p=0.029) and blood try?ac-IPR003033). glucose (R=0.3438, p=0.004) in fed P. obesus. There were no differences in gene expression between the fasted groups, EXAMPLE 49 and no correlations with phenotypic variables. EXAMPLE 53 Role in Disease 0362 SCP-2 levels are altered in diseases where lipid cDNA Microarray Production metabolism is abnormal. Such as diabetes, Zellweger, 0368 RNA extracted from P. obesus was used to generate Niemann Pick C (NPC) and atherosclerosis (Stolowich et a cDNA library in the pCMV-SPORT 6 Vector (Invitrogen al., 2002). SCP-2 is present in low levels in Zellweger Life Technologies). Individual clNA clones were arrayed syndrome but is not causal of this syndrome in which the into 384 well plates (The Australian Genome Research cells are deficient in peroxisomes (SCP2 Genecard recod, Facitlity, Queensland, Australia). The clones were then PCR Genecards Website, Weizmann Institute of Science). Zell amplified using vector complimentary primers (SP6 5'ATT weger patients have no detectable 15 kDa pro-SCP-2 protein TAG GTG ACA CTA TAG 3 SEQ ID NO:10): T7: or the mature 13 kDa SCP-2 and are deficient in very long 5'-TAATACGACT CACTATAGGG-3 SEQ ID NO:11). chain fatty acid oxidation (Wirtz, Biochem. J. 324(2): 353 PCR amplification of each clone was performed in a Gene 360, 1997: van Heusden et al., J. Biol. Chem. 265(7): Amp PCR System 9700 thermal cycler (PE Applied Bio 4105-41 10, 1990). Systems, Sunnyvale, Calif.) for 35 cycles of denaturation at 95° C. for 30 sec, annealing at 56° C. for 30 sec and 0363) The SCP-X/SCP-2 gene was investigated as a extension at 72° C. for 120 sec. A final extension step was candidate gene for infantile neuronal ceroid lipofuscinosis. perfonned at 72° C. for 5 min. Products were visualized by However, despite the gene mapping to the same chromo TAE agarose gel (1.5% w/v) electrophoresis at 6 V/cm for Somal location as markers for this disease, no association 90 min to ensure Successful amplification had taken place. could be found between mutations in the SCP-2/SCP-X gene 0369 PCR products were purified using the ArrayIt and the disease (Vesa et al., 1994). vacuum manifold system (TeleChem International, Sunny 0364 NPC1 disease is caused by a mutation in the NPC Vale, Calif.) and resuspended in 20 LL of 1x spotting protein. In this disease cholesterol accumulates in liver solution (TeleChem) at a concentration of 0.5 mg/ml in 384 lysosomes and the Golgi. This disease shows markedly well plate format. 5 uL of the resuspended purified cDNA reduced levels of hepatic 13 kDa SCP-2 as well as accu solution was transferred to 384 well uniplates (Whatman mulation of lipids in lysosomes and Golgi (Roff et al., J. Inc., Clifton, USA). This cDNA was arrayed onto Super Biol. Chem. 267(22): 15902-15908, 1992). Amine Microarray Substrates (TeleChem) using a Chip Writer Pro robotic arrayer (Virtek, Toronto, Canada) fitted EXAMPLE SO with 16 Stealth SMP-03 quill tipped microarray pins (Telechem). The distance between adjacent clNA spots was Relationship to Obesity or Diabetes 200 uM. Each pin drew 0.25 uL of cDNA and deposited approximately 0.6 mL on each slide. Humidity was main 0365 Streptozotocin-induced diabetes in rats decreased tained between 55-65% during printing. Approximately liver levels of SCP-2 by 60-90% and ovarian levels by 60% 12,000 elements were printed per microarray. Spotted DNAS (McLean et al., Biol. Reprod. 55(1): 38-46, 1996). Reduced were allowed to dry overnight, after which the slides were 13 kDa SCP-2 expression in pregnant diabetic mice was washed and blocked as recommended by the manufacturer associated with pregnancy loss (McLean et al., 1996). (TeleChem). US 2007/0021589 A1 Jan. 25, 2007 56

EXAMPLE 54 Human Cot1 DNA (Invitrogen Life Technologies). The cDNAs were again concentrated with Microcon 30 spin RNA Extraction columns (Millipore). The cDNA was hybridized in a 40 uL volume containing the labeled cDNA, 20xSSC, 8 Jug 0370 Total RNA was extracted from tissue in a two-step PolydA, 2.5x Denhardt’s solution, 4 lug yeast tRNA and 10% process utilising Trizol (Invitrogen Life Technologies, w/v SDS. The cDNA was then denatured at 98° C. for 2 min Carlsbad, USA) and RNeasy (Qiagen, Hilden, Germany) and maintained at 60° C. until required. 38 uL of the protocols. The tissue samples were lysed in 1.5 ml of Trizol hybridization Solution was applied to a cover slip and then (Invitrogen Life Technologies) and homogenised using a mounted onto an array slide. Hybridization was conducted Ystral Homogeniser (model D-7801, Dottingen, Germany). in a humid hybridisation chamber, in a hybridization oven, 300 uL of chloroform was added to the homogenate, which at 60° C. for 16 hours. Following hybridization the array was then mixed, transferred into a fresh 2 ml tube and slides were removed from their chamber and washed for 2 incubated at room temperature for 3 min. The homogenates min in each of a 0.5xSSC and 0.1% w/v SDS, 0.5xSSC and were then separated by centrifugation at 13 000xg for 15 0.01% w/v SDS, 0.6xSSC and 0.06% w/v SDS solution. The min (4° C.). Following centrifugation the aqueous Superna array slides were dried in a centrifuge for 1 min at 500xg. tant was collected in 2 ml tubes and an equal volume of 70% V/v ethanol added, with the solution mixed by pipetting. 700 EXAMPLE 56 LL of the sample was then transferred via pipette into RNeasy kit mini spin columns (Qiagen) placed in 2 ml tubes Image Acquisition and Data Analysis (Supplied) for purification. Initially the sample was centri 0374 Fluorescent images of the microarrays were fuged at 10 000xg for 20 sec. The flow-through was then acquired using a Scan Array Lite confocal laser Scanner poured back into the column and the centrifngation repeated. (Perkin Elmer) or GenePix 4000B scanner (Axon Instru Further purification was performed according to manufac ments) and the images were analysed using GenePix Pro 4.0 turer's instructions and the RNA was eluted using RNAase and Acuity 2.0 (Axon Instruments) and GeneSight 3.0 free water. (Biopiscovery, Sunnyvale, Calif.). Slides were scanned for both Cy3 and Cy5 signal at a 10 uM pixel resolution. Laser 0371. Following purification, total RNA integrity, quan intensity and amplification of the photomultiplier tubes were tity and concentration was assessed using the RNA 6000 adjusted to ensure approximately equal overall signal inten Nano Assay (Agilent Technologies, Palo Alto, USA) with sity for both Cy3 and Cy5. Data obtained from the scanner the Agilent 2100 Bioanalyser (Agilent Technologies) as per was imported into Gene Pix Pro (Version 4.0, Axon Instru the manufacturers instructions. This system utilises capil ments). False colour images were generated for each dye and lary electrophoresis to separate and detect nucleic acid combined to provide a representation of the relative Cy3 and fragments by size through the interconnected micro channels Cy5 intensities. Individual cDNA spots were flagged if spot on a Nano chip (Agilent Technologies). Good quality RNA size was too small, if the overall signal intensity was too low, is signified by an electropherogram displaying a marker or if the Cy3 and Cy5 signal intensities within the spots were peak, and two ribosomal peaks of which the 18s band is at not linearly related. GenePix allows for the “flagging of bad an approximate ratio of 1:2 to the 28s band. elements (defined by present GenePix parameters as feature signal intensity; feature background; element morphology; EXAMPLE 55 elements size and the percentage of pixels greater than feature background) that were then excluded from further Indirect Labeling of cDNA analysis. 0372 Fluorescently labelled cDNA was prepared from 0375 Median Cy3 and Cy5 signal intensities for each 20 ug of total RNA using an indirect labelling method. cDNA spot were imported from Genepix and data transfor cDNA synthesis was performed in a 30 uL reaction contain mation conducted using Genesight (Version 3.0, BioDiscov ing 5 ug oligo-dT primer, 400U SuperScript (Invitrogen), ery Inc, Los Angeles, USA). Signal intensities were cor 1x first strand buffer, 0.01 M DTT, 0.5 mM of each dATP, rected for local background and low expression values were dCTP and dGTP, 0.150 mM dTTP (Amersham, Bucking omitted. The ratio of Cy3 to Cy5 was calculated and the data hamshire, UK) and 0.2 mM aminoallyl-dUTP (Sigma, St. logarithmically transformed (base2). Signal intensity was Louis, Mo.). Synthesis was conducted in a Gene Amp PCR normalized to the mean intensity of all respective signal System 9700 (PE Applied Systems) at 42° C. for 2 hours. intensities, providing a relative measure of gene expression The reaction was stopped by addition of 5 uL of 0.5 M for each element on the microarray slide. Gene expression EDTA and RNA was hydrolyzed by addition of 20 ul of 1 M analysis between control animals and animals separated for NaOH at 70° C. for 20 minutes. The reaction was neutralized 4 days was assessed using an independent samples t-test. with 25uL of 1 M HEPES and the cDNA was purified using Differential gene expression as measured by microarray was QIAGEN PCR purification kits according to manufacturers screened for significance at p-0.05. instructions and eluted in nuclease-free water. The cDNA 0376 Those skilled in the art will appreciate that the was concentrated using Microcon30 spin columns (Milli invention described herein is susceptible to variations and pore, Bedford, Mass.) and the volume retrieved dried down modifications other than those specifically described. It is to under vacuum. The cDNA pellet was resuspended in 0.09 M be understood that the invention includes all such variations sodium bicarbonate and coupled to Cy3 or Cy5 monofunc and modifications. The invention also includes all of the tional NHS ester reactive dye (Amersham). The coupling steps, features, compositions and compounds referred to or reaction was conducted in the dark for 1 hour. indicated in this specification, individually or collectively, 0373) Dye-coupled cDNA was purified using Qiagen and any and all combinations of any two or more of said PCR purification columns, combined and added to 10 ug of steps or features. US 2007/0021589 A1 Jan. 25, 2007 57

BIBLIOGRAPHY 0394 Collier et al., Development of obesity and insulin resistance in the Israeli sand rat (Psammomys obesus). Does 0377 Altschul et al., Nucl. Acids Res. 25: 3389, 1997. leptin play a role?Ann. New York Acad. Sci. 827. 50-63, 0378 Antonenkov et al., Isolation and subunit composi 1997a. tion of native sterol carrier protein 2/3-oxoacyl-coenzyme A 0395 Collier et al., Exp. Clin. Endocrinol. Diabetes 105: thiolase from normal rat liver peroxisomes. Protein Expr 36-37, 1997b. DBH4 record from Pfam database of protein Purif. 18(3):249-256, 2000. families Website, Sanger Centre http://www.sanger.ac.uk/ 0379 Antonenkov et al., Substrate specificities of cgi-bin/Pfam/Swisspfamget.pl?name-DHB4 HUMAN 3-oxoacyl-CoA thiolase A and sterol carrier protein 2/3- oxoacyl-CoA thiolase purified from normal rat liver peroxi 0396 Dunstan et al., The Australian Diabetes, Obesity somes. Sterol carrier protein 2/3-oxoacyl-CoA thiolase is and Lifestyle Study (AusLiab)—methods and response involved in the metabolism of 2-methyl-branched fatty acids rates. Diabetes Res. Clin. Pract. 57: 119-129, 2002. and bile acid intermediates. J. Biol. Chem. 272(41): 26023 0397) Ferdinandusse et al., Peroxisomal fatty acid oxida 26031, 1997. tion disorders and 58 kDa sterol carrier protein X (SCPx). 0380 Atshaves et al., Expression and intracellular pro Activity measurements in liver and fibroblasts using a newly cessing of the 58 kDa sterol carrier protein-2/3-oxoacyl-CoA developed method. J Lipid Res. 41(3): 336-342, 2000. thiolase in transfected mouse L-cell fibroblasts. J Lipid Res. 0398 Festa et al., Elevated levels of acute-phase proteins 40(4): 610-622, 1999. and plasminogen activator inhibitor-1 predict the develop 0381 Australian Institute of Health and Welfare ment of type 2 diabetes: the insulin resistance atherosclero (AIWH), Australia's Health, 2002, Canberra: AIWH. sis study. 51(4): 1131-1137.2002. 0382 Ausubel et al. “Current Protocols in Molecular 0399 Fuchs et al., Disruption of the sterol carrier protein Biology” John Wiley & Sons Inc, Unit 19.3, Chapter 15, 2 gene in mice impairs biliary lipid and hepatic cholesterol 1994-1998. metabolism. J Biol Chem. 276(51): 48058-48065, 2001. 0383 Baker et al., Similarity between the amino-terminal 0400 Fuchs et al., Sterol carrier protein 2 participates in portion of mammalian 58-kD sterol carrier protein (SCPx) hypersecretion of biliary cholesterol during gallstone for and Escherichia coli acetyl-CoA acyltransferase: evidence mation in genetically gallstone-susceptible mice. Biochem J. for a gene fusion in SCPx. DNA Cell Biol 10(9): 695-698, 336(1): 33-37, 1998. 1991. 0401 Hofstedt et al., The common -675 4G/5G poly 0384 Barnes et al., The Caenorhabditis elegans behav morphism in the plasminogen activator inhibitor-1 gene is ioral gene unc-24 encodes a novel bipartite protein similar to strongly associated with obesity. Diabetologia 45(4): 584 both erythrocyte band 7.2 (stomatin) and nonspecific lipid 587, 2002. transfer protein. J. Neurochem. 67(1): 46-57, 1996. 0402 Human SCP-2 (NLTP HUMAN) record from 0385 Barnett et al., Diabete Nutr Metab. 8: 42-47, 1995. SWISS-PROT database, ExPasy Website http://krexipasy .org/cgi-bin/niceprot.pl?P22307 0386 Barnett et al. A cross-sectional and short-term longitudinal characterisation of NIDDM in Psammomys 0403 Interpro database of proteins http://www.ebi.ac.uk/ obesus. Diabetologia 377: 671-676, 1994a. interpro/IEntry?ac=IPR003033 0387 Barnett et al., The effect of restricting energy intake 0404 Ito et al., Hepatic cholesterol metabolism in on diabetes in Psammomys obesus. Int. J. Obesity 18: patients with cholesterol gallstones: enhanced intracellular 789-794, 1994b. transport of cholesterol. Gastroenterology 110(5): 1619 0388 Baum et al., Regulation of sterol carrier protein-2 1627, 1996. gene expression in rat liver and Small intestine. J. Lipid Res. 04.05 Jiang et al., Ahi-1, a novel gene encoding a modu 34(5): 729-739, 1993. lar protein with WD40-repeat and SH3 domains, is targeted 0389 Bhattacharjee et al., Genomic organization and by the Ahi-1 and Mis-2 provirus integrations. J. Virol. chromosomal localization of the ASnal gene, a mouse 76(18): 9046-9059, 2002. homologue of a bacterial arsenic-translocating ATPase gene. 0406 Kalaydjieva et al., N-myc downstream-regulated Gene 272: 291-299, 2001. gene 1 is mutated in hereditary motor and sensory neuropa 0390 Bonner and Laskey, Eur: J. Biochem. 46: 83, 1974. thy-Lom. Am. J. Hum. Genet. 67(1): 47-58, 2000. 0391 Bouchard, The genetics of Obesity, Boca Raton: 04.07 Kannenberg et al., Aberrant oxidation of the cho lesterol side chain in bile acid synthesis of sterol carrier CRC Press, 1994. protein-2/sterol carrier protein-X knockout mice. J Biol 0392 Boulkroun et al., Characterization of rat NDRG2 Chem. 274(50): 35455-35460, 1999. (N-myc downstream-regulated gene 2), a novel early min 0408 Kawata et al., Modulation of cholesterol 7 alpha eraldcorticoid-specific induced gene. J. Biol. Chem. hydroxylase activity by nonspecific lipid transfer protein in 277(35): 31506-31515, 2002. human liver--possibly altered regulation of its cytosolic 0393 Bun-ya et al., Thiolase involved in bile acid for level in patients with gallstones. Clin Chim Acta. 197(3): mation. J Biochem (Tokyo) 123(2): 347-352, 1998. 201-208, 1991. US 2007/0021589 A1 Jan. 25, 2007

0409 Kopelman et al., ASO consensus statement on 0427 Olsen and Uhler, Inhibition of protein kinase-A by obesity. UK Association for the Study of Obesity, Int. J. overexpression of the cloned human protein kinase inhibitor. Obesity 18: 188-191, 1994. Molec. Endocr: 5: 1246-1256, 1991. 0410 Kopelman, Obesity as a medical problem. Nature 0428 Ossendorp et al., Tissue-specific distribution of a 404: 635-643, 2000. peroxisomal 46-kDa protein related to the 58-kDa protein (sterol carrier protein X; sterol carrier protein 2/3-oxoacyl 0411 Kurdi-Haidar et al., Isolation of the ATP-binding CoA thiolase). Arch Biochem Biophys. 334(2): 251-260, human homolog of the arSA component of the bacterial 1996. arsenite transporter. Genomics 36: 486-491, 1996. 0429 Pandolfi et al., Plasminogen activator inhibitor type 0412 Kurdi-Haidar et al., Biochemical characterization 1 is increased in the arterial wall of type II diabetic subjects. of the human arsenite-stimulated ATPase (haSNA-I). J. Biol. Chem. 273: 22173-22176, 1998a. Arterioscler Thomb. Vasc. Biol 21 (8): 1378-1382, 2001. 0430 Puglielli et al., Modulation of intrahepatic choles 0413 Kurdi-Haidar et al., Dual cytoplasmic and nuclear terol trafficking: evidence by in vivo antisense treatment for distribution of the novel arsenite-stimulated human ATPase the involvement of sterol carrier protein-2 in newly synthe (hASNA-I). J. Cell Biochem. 71: 1-10, 1998b. sized cholesterol transport into rat bile. Biochem J. 317(3): 0414. Kurdi-Haidar et al., Chromosomal localization and 681-687, 1996. genomic structure of the human arsenite-stimulated ATPase 0431 Qu et al., Characterization and expression of three (hASNA-1). Somat. Cell Molec. Genet. 24: 307-311, 1998c. novel differentiation-related genes belong to the human 0415 Kurdi-Haidar et al., Immunohistochemical analysis NDRG gene family. Mol. Cell. Biochem. 229(1-2): 35-44, of the distribution of the human ATPase (bASNA-1) in 2002. normal tissues and its overexpression in breast adenomas and carcinomas. J. Histochem. Cytochem. 46:1243-1248, 0432 Ravussin, Metabolic differences and the develop 1998d. ment of obesity. Metabolism 44(3): 12-14, 1995. 0433 Roffet al., Deficiencies in sex-regulated expression 0416 Marmur and Doty, J. Mol. Biol. 5: 109, 1962. and levels of two hepatic sterol carrier proteins in a murine 0417 Marx, Unraveling the causes of diabetes. Science model of Niemann-Pick type C disease. J Biol Chem. 296: 686-689, 2002. 267(22): 15902-15908, 1992. 0418 Mavri et al., Subcutaneous abdominal, but not 0434 Samad et al., Insulin continues to induce plasmi femoral fat expression of plasminogen activator inhibitor-1 nogen activator inhibitor 1 gene expression in insulin (PAI-1) is related to plasma PAI-1 levels and insulin resis resistant mice and adipocytes. Mol. Med. 6(8): 680-692, tance and decreases after weight loss. Diabetologia 44(11): 2OOO. 2025-2031, 2001. 0435 Schroeder et al., Probing the ligand binding sites of 0419 McLean et al., Altered ovarian sterol carrier protein fatty acid and sterol carrier proteins: effects of ethanol. expression in the pregnant streptozotocin-treated diabetic Biochemistry. 34(37): 11919-11927, 1995. rat. Biol Reprod. 55(1): 38-46, 1996. 0436 SCP2 Genecard record, Genecards Website, Weiz 0420 Mertens and Van Gaal, Obesity, haemostasis and mann Institute of Science http://bioinfo.weizmann.ac.il/ the fibrinqlytic system. Obes. Rev. 3(2): 85-101, 2002. cards-bin/carddisp?SCP2&search=scp2&suff=txt 0421) Mokdad et al., The spread of the obesity epidemic 0437 SCP-2 record from Pfam database of protein fami in the United States, 1991-1998. JAMA 282(16): 1519-1522, lies Website, Sanger Centre http://www.sanger.ac.uk/cgi 1999. bin/Pfam/getacc?PF02036 0422 Murphy and Schroeder, Sterol carrier protein-2 0438) Seedorf et al., Defective peroxisomal catabolism of mediated cholesterol esterification in transfected L-cell branched fatty acyl coenzyme A in mice lacking the Sterol fibroblasts. Biochim Biophy's Acta. 1345(3): 283-292, 1997. carrier protein-2/sterol carrier protein-X gene function. Genes Dev. 12(8): 1189-1201, 1998. 0423 Must et al., The disease burden associated with overweight and obesity. JAMA 282(16): 1523-1529, 1999. 0439) Seedorf et al., Sterol carrier protein-2. Biochim Biophy's Acta. 1486(1): 45-54, 2000. Review. 0424 National Health and Medical Research Council, Acting On Australia's weight. A strategy for the prevention 0440 Shafrir and Gutman, Psammomys obesus of the of overweight and obesity. Canberra: National Health and Jerusalem colony: a model for nutritionally induced, non Medical Research Council, 1996. insulin-dependent diabetes.J. Basic Clin. Physiol. Pharm. 4: 83-99, 1993. 0425 Ohba et al., The structure of the human sterol carrier protein X/sterol carrier protein 2 gene (SCP2). 0441 Starodub et al., Sterol carrier protein-2 localization Genomics 24: 370-374, 1994. in endoplasmic reticulum and role in phospholipid forma tion. Am J Physiol Cell Physiol. 279(4): C1259-1269, 2000. 0426 Okuda and Kondoh, Identification of new genes indr2 and ndr3 which are related to Ndr1/RTP/Drg1 but show 0442 Sterol Carrier Protein 2 record, OMIM Website distinct tissue specificity and response to N-myc. Biochem. http://www.ncbi.nlm.nih.gov/htbin-post/Omim/disp Biophys. Res. Commun. 266(1): 208-215, 1999. mim?184755 US 2007/0021589 A1 Jan. 25, 2007 59

0443 Szyperski et al., NMR determination of the sec SCPx in branched-chain fatty acid metabolism in perox ondary structure and the three-dimensional polypeptide isqmes. Biochem Biophy's Res Commun. 236(3): 565-569, backbone fold of the human sterol carrier protein 2. FEBS 1997. Lett. 335(1): 18-26, 1993. 0450 Welch et al., Assignment of the mouse sterol carrier 0444 Vaisanen et al. , Vaisanen S. B. Humphries S. E. protein gene (Scp2) to chromosome 4. Mammalian Gengine Luong L. A. Penttila I. Bouchard C. Rauramaa R. Regular 7: 624-625, 1996. exercise, plasminogen activator inhibitor-1 (PAI-1) activity 0451 Wirtz, Phospholipid transfer proteins revisited. and the 4G/5G promoter polymorphism in the PAI-1 gene. Biochem J. 324(2): 353–360, 1997. Review. Thomb. Haemost. 82(3): 1117-1120, 1999. 0452 World Trade Organisation. Obesity. Preventing and 0445 van Heusden et al., Chinese hamster ovary cells managing the global epidemic. Report of a WHO Consul deficient in peroxisomes lack the nonspecific lipid transfer tation on Obesity. Geneva: World Health Organisation, protein (sterol carrier protein 2). J Biol Chem. 265(7): 1998. 4105-4510, 1990. 0453 Yamamoto et al., Cloning and expression of a 0446 Vesa et al., Assignment of sterol carrier protein cDNA encoding human sterol carrier protein 2. Proc Natl X/sterol carrier protein 2 to 1p32 and its exclusion as the Acad Sci USA. 88(2): 463-467, 1991. causative gene for infantile neuronal ceroid lipofuscinosis. 0454 Yamamoto, Localization of human sterol carrier Hum. Molec. Genet. 3: 341-346, 1994. protein 2 gene and cDNA expression in COS-7 cells. Hok 0447 Walder et al., The effect of dietary energy restric kaido Igaku Zasshi 67: 839-848, 1992. tion on body weight gain and the development of noninsu 0455 Zanlungo et al., Sterol carrier protein 2 gene trans lin-dependent diabetes mellitus (NIDDM) in Psammomys fer changes lipid metabolism and enterohepatic sterol cir obesus. Obesity Res. 5:-193-200, 1997a. culation in mice. Gastroenterology. 119(6): 1708-1719, 0448 Wanders et al., Identification of the newly discov 2OOO. ered 58 kDa peroxisomal thiolase SCPx as the main thiolase 0456 Zhou et al., Characterization of the human NDRG involved in both pristanic acid and trihydroxycholestanoic gene family: a newly identified member, NDRG4, is spe acid oxidation: implications for peroxisomal beta-Oxidation cifically expressed in brain and heart. Genomics 73(1): disorders. J Inherit Metab Dis. 21(3): 302-305, 1998. 86-97, 2001. 0449) Wanders et al., Sterol carrier protein X (SCPx) is a 0457 Zimmet, Kelly West Lecture 1991. Challenges in peroxisomal branched-chain beta-ketothiolase specifically diabetes epidemiology from West to the rest. Diabetes reacting with 3-oxo-pristanoyl-CoA: a new, unique role for Care 15:232-252, 1992.

SEQUENCE LISTING

<160> NUMBER OF SEQ ID NOS : 13 <210> SEQ ID NO 1 <211& LENGTH 426 &212> TYPE DNA <213> ORGANISM: Psammomys obesus &22O > FEATURE <221> NAME/KEY: misc feature <222> LOCATION: (336).. (336) <223> OTHER INFORMATION: n = any nucleotide <400 SEQUENCE: 1 gga catcttt to agc catga ggagctttct ggaaacticgg agttgataca gaaatatagg 60 aatataatca cqcaggotcc talacctggag aa cattgagc totactggaa cagotacaac 120 aac cqcc gag acct gaactt cqagc gaggt ggtgagatga coctoaagtg ccct gtgatg 18O citggtggtag gagaccalagc goctoat gag gatgcc.gtgg toggagtgtaa citcaaaactg 240 gaccc.cacac agaccitcgtt cotcaagatg gotgattctg gaggtoagcc acagot gacc 3OO cagoc aggca agctdactga ggctttcaag tacttinctgc aagg catggg ctacatggcc 360 to citcctgca toacticgcct atcgaggtot cqcacgg cat citttgaccag cqcago atcc 420

attgat 426

<210> SEQ ID NO 2 &2 11s LENGTH 451 US 2007/0021589 A1 Jan. 25, 2007 60

-continued

&212> TYPE DNA <213> ORGANISM: Psammomys obesus <400 SEQUENCE: 2 gctggtaccg gtc.cggaatt cocgggatat cqtcga.ccca cqcgtc.cggt ggtggagaag 60 atc.gcticcitg cc.gtggttca cattgaactg. tatcgcaaac titcctttct c galagagg gag 120 gtgc.ca.gtgg cqagtggg to C ggatttatc gtgtctgagg atggactgat tdtgaccaat 18O gctoacgtgg taccaacaa aaa.caggg to aaggttgagc tigaagaatgg agcaaccitat 240 gaagctaaaa toaaggatgt ggatgaaaag goaga catcg cacttatcaa aattgaccac 3OO cagggaaagc tigc.cagtc.tt gctgctgggc cqc to citcag agctt.cg acc aggagagttt 360 gtggtogcca toggaa.gc.cc cittitt.cccitt caaaacacag to accactgg gatcgtoagt 420 accaccCagc gaggcggcaa agagctgggg C 451

<210> SEQ ID NO 3 &2 11s LENGTH 478 &212> TYPE DNA <213> ORGANISM: Psammomys obesus <400 SEQUENCE: 3 tgacatttitc tittccaccitc titatgatago toatatatac taaatctitta tacagaaatg 60 tdag tactitg aacaaattica aaacacattg gtttattaac ttittggctca to catggittt 120 attaggttca aattatacct gattdatcta tatttactitt taaaatgtgt g gtttccitca 18O ttittaaaagt aaaactaaac agtgcttittg gaatttctaa got actaatt gttgatagat 240 acagotctgtg totagtaaaa tagttttgttg ggtgtgg gtt citatcttitcc atgaaaaagt 3OO gggaggtgta agittagtttg gttagtgcct aatagittaaa tittatataaa ataagaatga 360 gcatttggta totgitatgaa agggcc.ctaa atcaaaatga ttatccataa totaatctitta 420 ttcttgttitt ataaaaacca aaggg cactc attggittaag totgctgaga tagaaaag 478

<210> SEQ ID NO 4 &2 11s LENGTH 1884 &212> TYPE DNA <213> ORGANISM: Psammomys obesus &220s FEATURE <221 NAME/KEY: misc feature <222> LOCATION: (609) . . (609) <223> OTHER INFORMATION: n = any nucleotide &220s FEATURE <221 NAME/KEY: misc feature <222> LOCATION: (611) . . (611) <223> OTHER INFORMATION: n = any nucleotide &220s FEATURE <221 NAME/KEY: misc feature <222> LOCATION: (1388) . . ( 1388) <223> OTHER INFORMATION: n = any nucleotide &220s FEATURE <221 NAME/KEY: misc feature <222> LOCATION: (1390) . . (1390) <223> OTHER INFORMATION: n = any nucleotide &220s FEATURE <221 NAME/KEY: misc feature <222> LOCATION: (1413) . . (1413) <223> OTHER INFORMATION: n = any nucleotide &220s FEATURE <221 NAME/KEY: misc feature <222> LOCATION: (1512) . . (1512) <223> OTHER INFORMATION: n = any nucleotide &220s FEATURE <221 NAME/KEY: misc feature

US 2007/0021589 A1 Jan. 25, 2007 62

-continued <222> LOCATION: (385) . . (385) <223> OTHER INFORMATION: n = any nucleotide &220s FEATURE <221 NAME/KEY: misc feature <222> LOCATION: (416) ... (416) <223> OTHER INFORMATION: n = any nucleotide &220s FEATURE <221 NAME/KEY: misc feature <222> LOCATION: (430) ... (430) <223> OTHER INFORMATION: n = any nucleotide &220s FEATURE <221 NAME/KEY: misc feature <222> LOCATION: (507) . . (507) <223> OTHER INFORMATION: n = any nucleotide &220s FEATURE <221 NAME/KEY: misc feature <222> LOCATION: (754) . . (754) <223> OTHER INFORMATION: n = any nucleotide &220s FEATURE <221 NAME/KEY: misc feature <222> LOCATION: (856) . . (856) <223> OTHER INFORMATION: n = any nucleotide &220s FEATURE <221 NAME/KEY: misc feature <222> LOCATION: (928) ... (928) <223> OTHER INFORMATION: n = any nucleotide &220s FEATURE <221 NAME/KEY: misc feature <222> LOCATION: (980) ... (980) <223> OTHER INFORMATION: n = any nucleotide &220s FEATURE <221 NAME/KEY: misc feature <222> LOCATION: (1165) . . (1165) <223> OTHER INFORMATION: n = any nucleotide &220s FEATURE <221 NAME/KEY: misc feature <222> LOCATION: (1200) . . (1200) <223> OTHER INFORMATION: n = any nucleotide &220s FEATURE <221 NAME/KEY: misc feature <222> LOCATION: (1273) . . (1273) <223> OTHER INFORMATION: n = any nucleotide &220s FEATURE <221 NAME/KEY: misc feature <222> LOCATION: (1284) . . (1284) <223> OTHER INFORMATION: n = any nucleotide &220s FEATURE <221 NAME/KEY: misc feature <222> LOCATION: (1303) . . (1303) <223> OTHER INFORMATION: n = any nucleotide &220s FEATURE <221 NAME/KEY: misc feature <222> LOCATION: (1305) . . (1305) <223> OTHER INFORMATION: n = any nucleotide &220s FEATURE <221 NAME/KEY: misc feature <222> LOCATION: (1326) . . (1326) <223> OTHER INFORMATION: n = any nucleotide &220s FEATURE <221 NAME/KEY: misc feature <222> LOCATION: (1330) . . (1330) <223> OTHER INFORMATION: n = any nucleotide <400 SEQUENCE: 5 gttgggaaag aatgaagaaa caa.ccc.gatgaatagaaatgaaaag.ccitaa gocaaatgga 60 tittctgttga gatgttggat gaaaacaagt atccactgtt tacca acttig acgaaaaatc 120 tdaact gagg tittggctgtt aaaaaaaaaa attcactgtg gccitctgtgc titaattgtc.g 18O taalaccattg tactgttac togctoaaagt atcgtactgt to attagtaa citacatcaga 240 attgcaccgc tigctgttgga aaa.gc.caata aagaaac coc cag actocto citcagcaaat 3OO gttaataaag totg.cgcacci gtaggcct gt coacccagto: accalagcago gttc.cctttgt 360

US 2007/0021589 A1 Jan. 25, 2007 64

-continued <222> LOCATION: (527) . . (527) <223> OTHER INFORMATION: n = any nucleotide <400 SEQUENCE: 7 aaaattittac aaatgagtgt gaattgcatt citgatataat aattatcacc ccaccacact 60 tttactgaca citgttgatgg cctatoctogt gttitt cacat cacaattctt gtatggaaaa 120 atttctgtgg cct gtgtaac Coctotgg to agtattatga aaccalactat citttggtgat 18O aaataaggitt Coggtaagat gcc cagggitt catgagtatg gcacaaataa cagaggacag 240 gaggcctt.ca cqacgaagga gcc.cgtaagt ggcctggagg gcacagatgc agttcCaggit 3OO caagaaaaga gcagotttitt caa.caggcag totgtgggta to atgggaac toagcctgtc. 360 totgtagitta togacagogt ggcaggtgac totg.cccaca tottcctata cagtgcttitt 420 ttitt tact ga citggaagtac gtgaatctoa cittagtc.ccc aactggacgt tittctggaaa 480 aacaaagcaa atgttaaagt atgtc.tttct ggatataggc cagnagnaaa tacattalaga 540 atgagaggcc ttgctttgat citcago catt gaggctaga aaaaaattga aag galaccitt 600 cctgttgata gacitcaaagc cqtgaacaga agcct cittgg cct gtttcag acaatctotg 660 gtaatctact gacaatatoc aacagtttcg atgtc.cttgt ttaactaccc tagtagctitt 720 cittgttggatt togaagttcat ttittaaagct gtggaattitc aaactgaatt cacgtgcatt 78O ttgtaaaagt to agaaccag togctdagt.ct gtgtggcagg tttittitt cac cqcgtgatat 840 actattacaa atgcatgtgg toccatgctt gtottcaaat atataagtag togctaaatgg 9 OO ataagt cata toggagcttitt gatttag 927

<210 SEQ ID NO 8 &2 11s LENGTH 374 &212> TYPE DNA <213> ORGANISM: Psammomys obesus &220s FEATURE <221 NAME/KEY: misc feature <222> LOCATION: (60) . . (60) <223> OTHER INFORMATION: n = any nucleotide <400 SEQUENCE: 8 tgagatagot acticcataag cct citgaaga gcaatagota atttattatt act gtaattin 60 ttittaaaggc tittaaagtgc citcgggggitt cottgaaact aattittctac ttctgggatt 120 ccctggattc tittataagag atggtgacat gacitagg gala attctttittt tag tatgaaa 18O attgtc.ccitt caatacttitt citcttactgg cattgaatta totacagagac agaaaattgg 240 taattitttitt aatttctaac totcccagaa aactcctcitt gcctagtatt tatttgatgt 3OO gctttalacca togg gaggagg g g toggggggg gaact cattcaagct gccag tattittgatc 360 taca acct gt agca 374

<210 SEQ ID NO 9 <211& LENGTH: 402 &212> TYPE DNA <213> ORGANISM: Psammomys obesus &220s FEATURE <221 NAME/KEY: misc feature <222> LOCATION: (71) . . (71) <223> OTHER INFORMATION: n = any nucleotide &220s FEATURE <221 NAME/KEY: misc feature <222> LOCATION: (91)... (91) <223> OTHER INFORMATION: n = any nucleotide US 2007/0021589 A1 Jan. 25, 2007 65

-continued

&220s FEATURE <221 NAME/KEY: misc feature <222> LOCATION: (113) . . (113) <223> OTHER INFORMATION: n = any nucleotide &220s FEATURE <221 NAME/KEY: misc feature <222> LOCATION: (388) ... (388) <223> OTHER INFORMATION: n = any nucleotide

<400 SEQUENCE: 9 cccacgcagt cogggtggct citgcago.aca atttagg cct toggaggagct gtggttgtca 60 cc citctacaa natgggct to coc galagogg incagotcctt cagaacacac can attitcgg 120 citgctoccac cagotctgca agg gatggat tdaaggccaa tottgtc.ttt aag gagatcg 18O agaagaagct togalagaggaa goggalacagt togtgaagaa gatcggtggg atttittgcct 240 tdaaagtgaa gacggCCCt ggaggcaaag aagcc acctg. g.gtggtggat gtgaagaatg 3OO gcaagg gatc cqtgct tccc aactcagata agaaggctga citgcacaatc accatggcc.g 360 actc.cgacitt gctggctctg atgactgnoa aaatgaacco to 4 O2

<210> SEQ ID NO 10 &2 11s LENGTH 18 &212> TYPE DNA <213> ORGANISM: artificial sequence &220s FEATURE <223> OTHER INFORMATION: primer SP6

<400 SEQUENCE: 10 atttaggtga cactatag 18

<210> SEQ ID NO 11 &2 11s LENGTH 2.0 &212> TYPE DNA <213> ORGANISM: artificial sequence &220s FEATURE <223> OTHER INFORMATION: primer T7

<400 SEQUENCE: 11 taatacgact cactataggg 20

<210> SEQ ID NO 12 <211& LENGTH 4 &212> TYPE PRT <213> ORGANISM: peptide

<400 SEQUENCE: 12 Glu Val Ser Cys 1

<210> SEQ ID NO 13 &2 11s LENGTH 10 &212> TYPE PRT <213> ORGANISM: peptide

<400 SEQUENCE: 13 Gly Thr Arg Ser Arg Ser His Thr Ser Glu 1 5 10 US 2007/0021589 A1 Jan. 25, 2007 66

1. An isolated nucleic acid molecule comprising a 2. The isolated nucleic acid molecule of claim 1 wherein sequence of nucleotides encoding or complementary to a the nucleic acid molecule comprises the nucleotide sequence sequence encoding a molecule or derivative or homolog as set forth in SEQ ID NO:1. thereof wherein said nucleic acid molecule is expressed in a 3. The isolated nucleic acid molecule of claim 1 wherein larger amount in hypothalamus tissue of obese animals the nucleic acid molecule comprises the nucleotide sequence compared to lean animals or in fasted animals compared to as set forth in SEQ ID NO:2. fed animals wherein the nucleic acid molecule is selected 4. The isolated nucleic acid molecule of claim 1 wherein from: the nucleic acid molecule comprises the nucleotide sequence (i) a nucleic acid molecule comprises a nucleotide as set forth in SEQ ID NO:3. sequence as set forth in SEQ ID NO:1 or a nucleotide 5. The isolated nucleic acid molecule of claim 1 wherein sequence having at least 40% identity thereto or a the nucleic acid molecule comprises the nucleotide sequence nucleotide sequence capable of hybridizing to SEQ ID as set forth in SEQ ID NO: NO:1 or its complementary form under low stringency 6. The isolated nucleic acid molecule of claim 1 wherein conditions; the nucleic acid molecule comprises the nucleotide sequence as set forth in SEQ ID NO:5. (ii) a nucleic acid molecule comprises a nucleotide as set 7. The isolated nucleic acid molecule of claim 1 wherein forth in SEQID NO:2 or a nucleotide sequence having the nucleic acid molecule comprises the nucleotide sequence at least 40% identity thereto or a nucleotide sequence as set forth in SEQ ID NO:6. capable of hybridizing to SEQID NO:2 or its comple 8. The isolated nucleic acid molecule of claim 1 wherein mentary form under low stringency conditions; the nucleic acid molecule comprises the nucleotide sequence (iii) a nucleic acid molecule comprises a nucleotide as set forth in SEQ ID NO:7. sequence as set forth in SEQ ID NO:3 or a nucleotide 9. The isolated nucleic acid molecule of claim 1 wherein sequence having at least 40% identity thereto or a the nucleic acid molecule comprises the nucleotide sequence nucleotide sequence capable of hybridizing to SEQ ID as set forth in SEQ ID NO:8. NO:3 or its complementary form under low stringency 10. The isolated nucleic acid molecule of claim 1 wherein conditions; the nucleic acid molecule comprises the nucleotide sequence (iv) a nucleic acid molecule comprises a nucleotide as set forth in SEQ ID NO:9. sequence as set forth in SEQ ID NO:4 or a nucleotide 11. An isolated molecule comprising a sequence of nucle sequence having at least 40% identity thereto or a otides or amino acids encoded by a nucleic acid molecule nucleotide sequence capable of hybridizing to SEQ ID which is expressed in a larger amount in hypothalamus NO:4 or its complementary form under low stringency tissue of obese animals compared to lean animals or in fasted conditions; animals compared to fed animals wherein the isolated mol ecule is encoded by a nucleic acid molecule selected from: (v) a nucleic acid molecule comprises a nucleotide sequence as set forth in SEQ ID NO:5 or a nucleotide (i) a nucleic acid molecule as set forth in SEQ ID NO:1 sequence having at least 40% identity thereto or a or a nucleotide sequence having at least about 40% nucleotide sequence capable of hybridizing to SEQ ID identity to SEQ ID NO:1 or a nucleotide sequence NO:5 or its complementary form under low stringency capable of hybridizing to SEQID NO:1 or its comple conditions; mentary form under low stringency conditions; (vi) a nucleic acid molecule comprises a nucleotide (ii) a nucleic acid molecule as set forth in SEQ ID NO:2 sequence as set forth in SEQ ID NO:6 or a nucleotide or a nucleotide sequence having at least about 40% sequence having at least 40% identity thereto or a identity to SEQ ID NO:2 or a nucleotide sequence nucleotide sequence capable of hybridizing to SEQ ID capable of hybridizing to SEQID NO:2 or its comple NO:6 or its complementary form under low stringency mentary form under low stringency conditions; conditions; (iii) a nucleic acid molecule as set forth in SEQID NO:3 (vii) a nucleic acid molecule comprises a nucleotide or a nucleotide sequence having at least about 40% sequence as set forth in SEQ ID NO:7 or a nucleotide identity to SEQ ID NO:3 or a nucleotide sequence sequence having at least 40% identity thereto or a capable of hybridizing to SEQID NO:3 or its comple nucleotide sequence capable of hybridizing to SEQ ID mentary form under low stringency conditions; NO:7 or its complementary form under low stringency conditions; (iv) a nucleic acid molecule as set forth in SEQID NO:4 or a nucleotide sequence having at least about 40% (viii) a nucleic acid molecule comprises a nucleotide identity to SEQ ID NO:4 or a nucleotide sequence sequence as set forth in SEQ ID NO:8 or a nucleotide capable of hybridizing to SEQID NO:4 or its comple sequence having at least 40% identity thereto or a mentary form under low stringency conditions; nucleotide sequence capable of hybridizing to SEQ ID NO:8 or its complementary form under low stringency (v) a nucleic acid molecule as set forth in SEQ ID NO:5 conditions; and or a nucleotide sequence having at least about 40% (ix) a nucleic acid molecule comprises a nucleotide identity to SEQ ID NO:5 or a nucleotide sequence sequence as set forth in SEQ ID NO:9 or a nucleotide capable of hybridizing to SEQID NO:5 or its comple sequence having at least 40% identity thereto or a mentary form under low stringency conditions; nucleotide sequence capable of hybridizing to SEQ ID (vi) a nucleic acid molecule as set forth in SEQID NO:6 NO:9 or its complementary form under low stringency or a nucleotide sequence having at least about 40% conditions. identity to SEQ ID NO:6 or a nucleotide sequence US 2007/0021589 A1 Jan. 25, 2007 67

capable of hybridizing to SEQID NO:6 or its comple larity to this sequence or a derivative, homolog, analog, mentary form under low stringency conditions; chemical equivalent or mimetic of said protein; (vii) a nucleic acid molecule as set forth in SEQID NO:7 (v) a protein encoded by a nucleotide sequence Substan or nucleotide sequence having at least about 40% tially as set forth in SEQ ID NO:5 or a derivative, identity to SEQ ID NO:7or a nucleotide sequence homolog or analog thereof or a sequence encoding an capable of hybridizing to SEQID NO:7 or its comple amino acid sequence having at least about 40% simi mentary form under low stringency conditions; larity to this sequence or a derivative, homolog, analog, chemical equivalent or mimetic of said protein; (viii) nucleic acid molecule as set forth in SEQ ID NO:8 or a nucleotide sequence having at least about 40% (vi) a protein encoded by a nucleotide sequence Substan identity to SEQ ID NO:8 or a nucleotide sequence tially as set forth in SEQ ID NO:6 or a derivative, capable of hybridizing to SEQID NO:8 or its comple homolog or analog thereof or a sequence encoding an mentary form under low stringency conditions; and amino acid sequence having at least about 40% simi larity to this sequence or a derivative, homolog, analog, (ix) a nucleic acid molecule set forth in SEQ ID NO:9 or a nucleotide sequence having at least about 40% iden chemical equivalent or mimetic of said protein; tity to SEQID NO:9 or a nucleotide sequence capable (vii) a protein encoded by a nucleotide sequence Substan of hybridizing to SEQ ID NO:9 or its complementary tially as set forth in SEQ ID NO:7 or a derivative, form under low stringency conditions. homolog or analog thereof or a sequence encoding an 12. The isolated molecule of claim 11 wherein the mol amino acid sequence having at least about 40% simi ecule is a protein. larity to this sequence or a derivative, homolog, analog, 13. The isolated protein of claim 12 encoded by a nucle chemical equivalent or mimetic of said protein; otide sequence set forth in SEQ ID NO:1. (viii) a protein encoded by a nucleotide sequence Sub 14. The isolated protein of claim 12 encoded by a nucle stantially as set forth in SEQ ID NO:8 or a derivative, otide sequence set forth in SEQ ID NO:2. homolog or analog thereof or a sequence encoding an 15. The isolated protein of claim 12 encoded by a nucle amino acid sequence having at least about 40% simi otide sequence as set forth in SEQ ID NO:3. larity to this sequence or a derivative, homolog, analog, 16. The isolated protein of claim 12 encoded by a nucle chemical equivalent or mimetic of said protein; otide sequence as set forth in SEQ ID NO:4. 17. The isolated protein of claim 12 encoded by a nucle (ix) a protein encoded by a nucleotide sequence substan otide sequence as set forth in SEQ ID NO:5. tially as set forth in SEQ ID NO:9 or a derivative, 18. The isolated protein of claim 12 encoded by a nucle homolog or analog thereof or a sequence encoding an otide sequence as set forth in SEQ ID NO:6. amino acid sequence having at least about 40% simi 19. The isolated protein of claim 12 encoded by a nucle larity to this sequence or a derivative, homolog, analog, otide sequence as set forth in SEQ ID NO:7 chemical equivalent or mimetic of said protein; 20. The isolated protein of claim 12 encoded by a nucle (X) a protein encoded by a nucleotide acid molecule otide sequence as set forth in SEQ ID NO:8. capable of hybridizing to the nucleotide sequence as set 21. The isolated protein of claim 12 encoded by a nucle forth in SEQ ID NO:1 or a derivative, homolog or otide sequence as set forth in SEQ ID NO:9. analog thereof under low stringency conditions; 22. An isolated protein selected from the list consisting of: (xi) a protein encoded by a nucleic acid molecule capable (i) a protein encoded by a nucleotide sequence Substan of hybridizing to the nucleotide sequence as set forth in tially as set forth in SEQ ID NO:1 or a derivative, SEQ ID NO:2 or a derivative, homolog or analog homolog or analog thereof or a sequence encoding an thereof under low stringency conditions; amino acid sequence having at least about 40% simi larity to this sequence or a derivative, homolog, analog, (xii) a protein encoded by a nucleic acid molecule capable of hybridizing to the nucleotide sequence as set forth in chemical equivalent or mimetic of said protein; SEQ ID NO:3 or a derivative, homolog or analog (ii) a protein encoded by a nucleotide sequence Substan thereof under low stringency conditions; tially as set forth in SEQ ID NO:2 or a derivative, homolog or analog thereof or a sequence encoding an (xiii) a protein encoded by a nucleic acid molecule amino acid sequence having at least about 40% simi capable of hybridizing to the nucleotide sequence as set larity to this sequence or a derivative, homolog, analog, forth in SEQ ID NO:4 or a derivative, homolog or chemical equivalent or mimetic of said protein; analog thereof under low stringency conditions; (iii) a protein encoded by a nucleotide sequence Substan (xiv) a protein encoded by a nucleic acid molecule tially as set fort in SEQ ID NO:3 or a derivative, capable of hybridizing to the nucleotide sequence as set homolog or analog thereof or a sequence encoding an forth in SEQ ID NO:5 or a derivative, homolog or amino acid sequence having at least about 40% simi analog thereof under low stringency conditions; larity to this sequence or a derivative, homolog, analog, (XV) a protein encoded by a nucleic acid molecule capable chemical equivalent or mimetic of said protein; of hybridizing to the nucleotide sequence as set forth in (iv) a protein encoded by a nucleotide sequence Substan SEQ ID NO:6 or a derivative, homolog or analog tially as set forth in SEQ ID NO:4 or a derivative, thereof under low stringency conditions; homolog or analog thereof or a sequence encoding an (Xvi) a protein encoded by a nucleic acid molecule amino acid sequence having at least about 40% simi capable of hybridizing to the nucleotide sequence as set US 2007/0021589 A1 Jan. 25, 2007 68

forth in SEQ ID NO:7 or a derivative, homolog or ment, heart diseas, inflammation, disorders associated with analog thereof under low stringency conditions; the immune system, infertility, disease associated with the brain, and metabolic energy levels, said method comprising (Xvii) a protein encoded by a nucleic acid molecule administering to said mammal an effective amount of an capable of hybridizing to the nucleotide sequence as set agent for a time and under conditions sufficient to modulate forth in SEQ ID NO:8 or a derivative, homolog or the expression of AGT-701, AGT-702, AGT-704, AGT-705, analog thereof under low stringency conditions; and AGT-706, AGT-707, AGT-708, AGT-709 and/or AGT-710. (Xviii) a protein encoded by a nucleic acid molecule 26. A method of treating mammal Suffering from a disease capable of hybridizing to the nucleotide sequence as set condition characterized by one or more symptoms of inter forth in SEQ ID NO:9 or a derivative, homolog or alia a myopathy, obesity, anorexia, weight maintenance, analog thereof under low stringency conditions. diabetes, inflammation, disorders associated with the 23. A method for modulating expression of one of AGT immune system, infertility, disease associated with the brain, 701, AGT-702, AGT-704, AGT-705, AGT-706, AGT-707; and/or metabolic energy levels, said method comprising AGT-708, AGT-709 and/or AGT-710 in a mammal, said administering to said mammal an effective amount of AGT method comprising contacting of AGT-701, AGT-702, AGT 701, AGT-702, AGT-704, AGT-705, AGT-706, AGT-707, 704, AGT-705, AGT-706, AGT-707, AGT-708, AGT-709 AGT-708, AGT-709 and/or AGT-710. and/or AGT-710 with an effective amount of a modulator of AGT-701, AGT-702, AGT-704, AGT-705, AGT-706, AGT 27-29. (canceled) 707, AGT-708, AGT-709 and/or AGT-710 expression for a 30. A composition comprising a modulator of AGT-701, time and under conditions Sufficient to up-regulate or down AGT-702, AGT-704, AGT-705, AGT-706, AGT-707, AGT regulate or otherwise modulate expression of AGT-701, 708, AGT-709 and/or AGT-710 expression AGT-701, AGT AGT-702, AGT-704, AGT-705, AGT-706, AGT-707, AGT 702, AGT-704, AGT-705, AGT-706, AGT-707, AGT-708, 708, AGT-709 and/or AGT-710. AGT-709 and/or AGT-710 activity and one or more phar 24. A method of modulating activity of AGT-701, AGT maceutically acceptable carriers and/or diluents. 702, AGT-704, AGT-705, AGT-706, AGT-707, AGT-708, 31. A method for detecting AGT-701, AGT-702, AGT AGT-709 and/or AGT-710 in a mammal, said method com 704, AGT-705, AGT-706, AGT-707 AGT-708, AGT-709 prising administering to said mammal a modulating effective and/or AGT-710 or a derivative or homolog thereof in a amount of a molecule for a time and under conditions biological sample from a subject, said method comprising sufficient to increase or decrease of AGT-701, AGT-702, contacting said biological sample with an antibody specific AGT-704, AGT-705, AGT-706, AGT-707, AGT-708, AGT for AGT-701, AGT-702, AGT-704, AGT-705, AGT-706, 709 and/or AGT-710 activity. AGT-707, AGT-708, AGT-709, AGT-710 or their antigenic 25. A method of treating a mammal Suffering from a derivatives or homologs for a time and under conditions condition characterized by one or more symptoms or imter Sufficient for a complex to form, and then detecting said alia a myopathy, obesity, anorexia, weight maintenance, complex. diabetes, disorders associated with mitochrondrial dysfunc tion, genetic disorders, cancer impaired muscle develop