Copyright  2004 by the Genetics Society of America

Molecular and Comparative Genetics of Mental Retardation

Jennifer K. Inlow*,1 and Linda L. Restifo*,†,‡,2 *Arizona Research Laboratories Division of Neurobiology, †Department of Neurology, ‡Genetics Graduate Interdisciplinary Program, University of Arizona, Tucson, Arizona 85721-0077 Manuscript received August 14, 2003 Accepted for publication November 14, 2003

ABSTRACT Affecting 1–3% of the population, mental retardation (MR) poses significant challenges for clinicians and scientists. Understanding the biology of MR is complicated by the extraordinary heterogeneity of genetic MR disorders. Detailed analyses of Ͼ1000 Online Mendelian Inheritance in Man (OMIM) database entries and literature searches through September 2003 revealed 282 molecularly identified MR genes. We estimate that hundreds more MR genes remain to be identified. A novel test, in which we distributed unmapped MR disorders proportionately across the autosomes, failed to eliminate the well-known X-chromosome overrepresentation of MR genes and candidate genes. This evidence argues against ascer- tainment bias as the main cause of the skewed distribution. On the basis of a synthesis of clinical and laboratory data, we developed a biological functions classification scheme for MR genes. Metabolic path- ways, signaling pathways, and transcription are the most common functions, but numerous other aspects of neuronal and glial biology are controlled by MR genes as well. Using protein sequence and domain- organization comparisons, we found a striking conservation of MR genes and genetic pathways across the million years that separate Homo sapiens and Drosophila melanogaster. Eighty-seven percent have one 700ف or more fruit fly homologs and 76% have at least one candidate functional ortholog. We propose that D. melanogaster can be used in a systematic manner to study MR and possibly to develop bioassays for therapeutic drug discovery. We selected 42 Drosophila orthologs as most likely to reveal molecular and cellular mechanisms of nervous system development or plasticity relevant to MR.

ENTAL RETARDATION (MR) is a common form clinical conditions affect such large numbers of children M of cognitive impairment affecting between 1 and and young adults and yet have no effective pharmacolog- 3% of the population of industrialized countries (Roele- ical therapy. One reason for the lack of drug treatments veld et al. 1997; Aicardi 1998). Although there is de- is the limited understanding of the molecular and cellu- bate over the definition and classification of MR (Leo- lar bases for MR. nard and Wen 2002), it is often defined by an IQ of Many environmental and genetic factors can cause Ͻ70, with deficits in adaptive skills included as diagnos- MR, including premature birth, prenatal infections, tic criteria (Luckasson et al. 1992; Daily et al. 2000). chromosomal abnormalities, and single-gene mutations Behavioral and cognitive therapies can help mentally (Kinsbourne and Graf 2000). An etiology can be estab- retarded patients reach their maximum potential (Bat- lished in 60–75% of cases of severe MR, but only in haee 2001; Butler et al. 2001), but they are not curative 38–55% of mild cases. Estimates of genetic causes of and often focus on treating habit disorders, aggression, severe MR range from 25 to 50% (McLaren and Bry- or self-injurious behavior that can accompany MR son 1987). There are two categories of hereditary MR. (Long and Miltenberger 1998; Dosen and Day 2001). Isolated MR with no other consistent defining features MR due to congenital hypothyroidism is now largely is known as nonspecific or nonsyndromal MR. To date, preventable through screening and hormone replace- all but one of these (Molinari et al. 2002) are X-linked, ment (Gruters et al. 2002). Aside from this, the only but other autosomal genes may have eluded identifica- molecular-based therapeutic approaches are dietary re- tion because of the considerably greater difficulty of strictions and supplements for inborn errors of metabo- mapping disorders to autosomal loci. MR also occurs, lism such as phenylketonuria (Dashman and Sansaricq with variable penetrance and expressivity, as a pheno- 1993; Levy 1999; Kabra and Gulati 2003). Few, if any, typic feature of numerous hereditary syndromes. The challenge of understanding the biological bases of he- reditary MR is heightened by its enormous genetic het- 1Present address: Department of Chemistry, Indiana State University, erogeneity and the limited knowledge of cellular pheno- Terre Haute, IN 47809. types in the brains of mentally retarded individuals. 2Corresponding author: Arizona Research Laboratories Division of Neurobiology, 611 Gould-Simpson Bldg., 1040 E. 4th St., University of Recent rapid progress in human genetics, however, has Arizona, Tucson, AZ 85721-0077. E-mail: [email protected] provided us with an opportunity for a comprehensive

Genetics 166: 835–881 ( February 2004) 836 J. K. Inlow and L. L. Restifo analysis of the biochemical and cellular processes under- MATERIALS AND METHODS lying the MR phenotype. A search for “mental retarda- Databases and bioinformatics tools: The OMIM database tion” in the Online Mendelian Inheritance in Man [McKusick-Nathans Institute for Genetic Medicine, Johns (OMIM) database (Hamosh et al. 2002) yields Ͼ1000 Hopkins University and National Center for Biotechnology entries, suggesting that hundreds of human genes can Information (NCBI), National Library of Medicine; Hamosh mutate to a MR phenotype. We conducted a detailed et al. 2002] was accessed online (http://www.ncbi.nlm.nih. gov/entrez/query.fcgi?dbϭOMIM) to search for genes and analysis to determine how many MR genes have been mental retardation disorders. BLASTP (Altschul et al. 1997) molecularly identified and what molecular and biologi- at the NCBI (http://www.ncbi.nlm.nih.gov/BLAST/) and cal functions they encode. the Homophila Human-Disease-to-Drosophila-Gene database Controversies over the definition of MR are based on (Reiter et al. 2001; http://homophila.sdsc.edu/) were used to search for D. melanogaster homologs of the human MR genes. both sociopolitical and biological considerations (Leo- Pairwise sequence alignments were performed with LALIGN nard and Wen 2002). Narrow definitions of MR restrict (http://www.ch.embnet.org/software/LALIGN_form.html; it to cases of nonprogressive cognitive impairment pres- Huang and Miller 1991). DotPlot and TransMem of the ent from birth and categorize as “dementia” cases of Accelrys GCG Wisconsin Package were accessed through the progressive cognitive deterioration beginning some Arizona Research Laboratories Biotechnology Computing Fa- cility and were used to compare homologous protein se- time after a period of normal development. Nonethe- quences by dot matrix analysis (Maizel and Lenk 1981) and less, hereditary neurodegenerative disorders are often prediction of transmembrane regions, respectively. The In- said to cause MR (see Stevenson et al. 2000), even terPro resource for protein families, domains, and sites when the onset is in late childhood or adolescence (e.g., (Apweiler et al. 2001; http://www.ebi.ac.uk/interpro/scan. progressive epilepsy with mental retardation, one of the html) was used to determine and compare the locations of functional domains in homologous proteins. The Gene Ontol- neuronal ceroid lipofuscinoses; CLN8). Moreover, the ogy (GO) database (Gene Ontology Consortium 2001) was distinction between MR and dementia blurs in disorders accessed online (http://www.geneontology.org/) to deter- such as Rett syndrome (MECP2), where phenotypes mine the molecular-function classification of MR gene prod- span a wide spectrum of severity and clinical course ucts. FlyBase (FlyBase Consortium 2002) was accessed on- (Hammer et al. 2002). For the purpose of our analysis line (http://flybase.bio.indiana.edu/) to obtain information on Drosophila genes. Newly isolated P-element insertions were of hereditary MR, we chose a broader, albeit less precise, found through the P-Screen Database (http://flypush.imgen. definition that includes progressive disorders with onset bcm.tmc.edu/pscreen/). of cognitive impairment in childhood and, occasionally, Identifying human mental retardation genes through as late as adolescence. OMIM: We searched all OMIM fields on February 21, 2002, In parallel with human genetics research, progress in using the phrase “mental retardation” and reviewed each of the resulting 1010 entries. To include very mild MR, we also Drosophila melanogaster genetics and genome sequencing searched for “cognitive impairment” and “learning disability,” (Adams et al. 2000) allows a comparative approach to obtaining 38 additional entries for evaluation. In retrospect, the biological study of MR. Not only do homologous “developmental delay” and “psychomotor retardation” would mammalian and fruit fly genes share biological func- have been useful search phrases as well. Other MR genes were identified by periodic literature searches through September tions (Padgett et al. 1993; Bonini et al. 1997; Johnston 30, 2003, using NCBI’s PubMed. et al. 1997; Leuzinger et al. 1998; Nagao et al. 1998; Careful evaluation of individual OMIM search results and Dearborn et al. 2002), but also Drosophila provides cross-referencing with literature-search results revealed both useful models of human disease, including spinocere- false positives and false negatives. OMIM contains many par- bellar ataxia (Warrick et al. 1998), Parkinson’s disease tially redundant entries, which makes it impossible to equate numbers of entries obtained from a search for a specific phe- (Feany and Bender 2000), Huntington’s disease (Jack- notype with the number of genes that can mutate to that son et al. 1998), and type 1 diabetes (Rulifson et al. phenotype. OMIM entries for a genetic disorder or gene are 2002). Moreover, neurodegeneration in the Drosophila organized into some or all of the following fields: title, MIM model of Huntington’s disease can be suppressed by number, gene map, clinical synopsis, text (literature sum- treatment with a specific peptide (Kazantsev et al. mary), allelic variants, references, and contributors. When different mutations of a single gene cause distinct disorders, 2002). Hence, we propose that this neurogenetic model there are separate OMIM entries for each disease, but only system can reveal cellular phenotypes responsible for one contains a list of disease-associated alleles (“allelic vari- hereditary MR and will provide bioassays for potential ants” field). For example, mutations in the L1CAM gene result drug therapies. By searching the Drosophila genome, in one of at least three MR disorders (Weller and Gartner we found candidate functional orthologs for the major- 2001): MASA syndrome (mental retardation, aphasia, shuf- fling gait, and adducted thumbs), HSAS (hydrocephalus due ity of molecularly identified human MR genes. Several to congenital stenosis of the aqueduct of Sylvius), or SPG1 dozen of these genes are most likely to have mutant (spastic paraplegia 1). There is a separate OMIM entry for phenotypes due to primary developmental defects of each of these disorders and a fourth entry for the L1CAM neurons or glia and thereby provide clues to the causes gene. There is some text redundancy among the four entries, but only the L1CAM entry includes the allelic variants field. and treatment of MR due to single-gene mutations. On the basis of this organizational scheme, OMIM searches Treatment strategies based on the understanding of restricted to entries containing the allelic variants field should hereditary MR may be useful for acquired MR as well. eliminate redundant results. However, this strategy would Molecular Genetics of Mental Retardation 837 cause false negatives because entries that list allelic variants Identifying Drosophila orthologs of human mental retarda- do not necessarily contain complete phenotype descriptions. tion genes: We used bioinformatics tools to determine if the For example, entry 600514, which lists the allelic variants of human MR genes have likely functional orthologs in D. melano- reelin (RELN), does not contain the phrase “mental retarda- gaster. For MR genes encoding tRNAs, we aligned the human tion,” whereas entry 257320 for Norman-Roberts type lis- and fly tRNA homologs using LALIGN and calculated the sencephaly syndrome due to RELN mutations contains the percentage identity. For each protein-coding MR gene, we search phrase but does not list allelic variants. In principle, searched the D. melanogaster sequences of the NCBI nonredun- the “clinical synopsis” field could offer a useful search strategy dant database with NCBI’s BLASTP. We used an E-value cutoff for disease phenotypes, but some are incomplete (e.g., the of 1 ϫ 10Ϫ10 (1e-10), a threshold commonly used for human- clinical synopsis for Norman-Roberts lissencephaly does not fly gene comparisons (Fortini et al. 2000; Lloyd et al. 2000; include MR although it is a consistent phenotype of this disor- Reiter et al. 2001). The Homophila database (Reiter et al. der) and many entries have no clinical synopsis at all. 2001) is designed for such comparisons but, due to its organi- Errors in the clinical synopsis fields also contributed to zational features and infrequent updates, we found it easier false-positive entries (see Table 1). For and more reliable to do our own BLAST searches. For one (%15ف) the many example, entries 167200 and 167210 for pachyonychia con- MR gene, we concluded that Drosophila does not have a genita types 1 and 2 include MR in their clinical synopses, biologically meaningful homolog despite a published claim but the only evidence for MR is in the much rarer type 4 of one. Grunge (FBgn0010825) is the most similar fly gene (Feinstein et al. 1988). Other false positives result from state- to human DRPLA (Zhang et al. 2002), but has a BLASTP ments such as “neither [patient] had evidence of mental retar- E-value of 5E-2, which does not meet our threshold. Moreover, dation” (entry 243605). In other entries MR is not a feature sequence similarity is limited to the extreme C terminus and of the disorder being described, but some atypical patients the Grunge protein does not possess the same domain organi- are mentally retarded due to deletion of adjacent genes (e.g., zation as DRPLA. entry 312865). Finally, MR may be mentioned because related For protein-coding MR genes, we also conducted a “reverse” disorders have a MR phenotype. For instance, MR is a pheno- BLASTP search using the top-scoring Drosophila BLASTP re- type of a subset of hereditary spastic paraplegias, so it is men- sult as a query against the human sequences of the NCBI tioned in the text of the entries for most forms. Boyadjiev and nonredundant database. A Drosophila gene was considered Jabs (2000) noted similar difficulties in extracting information an ortholog of a human MR gene only if this reverse analysis from OMIM. To obtain complete information from OMIM, (sometimes supplemented with dot-matrix plot and protein- one must search in a manner that yields redundant and irrele- domain comparison; see below) revealed that it was more vant entries. This minimizes false negatives, but, to interpret similar to the human MR gene (or a paralog) than to another the search results accurately, one must be willing to review gene. For example, the Drosophila proteins most similar to individual entries carefully. Even using a broad OMIM search human glial fibrillary acidic protein (GFAP) are the products strategy, we missed 45 MR genes that were revealed through of Lamin and Lamin C. A reverse BLASTP search revealed various literature search strategies. that, although these two proteins share a single common do- Functional classification of human mental retardation genes: main with GFAP, they are more similar over their full lengths We searched for the 282 MR gene products in the molecular- to members of the human lamin family. In addition, both function category of the GO database and used information human and Drosophila lamins are localized to the nucleus from the literature to classify those not yet in the database. (Goldman et al. 2002), whereas GFAP is cytoplasmic (Eng et al. The GO database is composed of three parallel schemes for 2000). Hence, GFAP does not have an ortholog in Drosophila. classifying gene function: biological process, cellular compo- When compared with mammals, Drosophila has relatively nent, and molecular function (Gene Ontology Consortium few duplicated genes (Durand 2003), so in some cases a 2001). Each ontology is a hierarchical classification scheme Drosophila gene is the single ortholog of a paralogous set of (directed acyclic graph) of structured vocabulary terms that human genes. For example, FMR1, which causes fragile X differs from a simple hierarchical tree, such as a pedigree, in syndrome, is a member of a gene family that also includes FXR1 that each term may be a “child” of multiple independent and FXR2, the autosomal fragile X-related genes. Drosophila “parents.” There are 24 occupied top-level terms in the molec- dfmr1 is the only homologous fly gene, sharing significant ular-function ontology, i.e., terms that do not have parents sequence similarity and domain structure with all three human themselves. When GO assigned gene products to multiple genes, suggesting that it is the sole ortholog. molecular functions, we chose the most specific term for each. ␣ To determine if orthologous genes are likely to share the For example, we classified the -subunit of Gs, the adenyl- same molecular and biological functions in humans and flies, ate cyclase-stimulating guanine nucleotide-binding protein we used dot matrix plots (GCG DotPlot) to assess the extent (GNAS), as a “nucleotide-binding protein” rather than as a of protein sequence similarity and searched the InterPro data- “hydrolase,” the other GO assignment. For genes considered base for known functional domains in each protein. GCG by GO to have “unknown function,” we found that most could TransMem was used to predict transmembrane regions in be provisionally classified on the basis of data in the literature. the human and fly proteins. If the proteins share sequence The “biological function(s)” assignments were based on similarity over most of their lengths and have similar organiza- literature reviews for each gene, including neuroimaging, tion of known functional domains, we considered them to be gene expression, and neuropathological data from human candidate functional orthologs. In some cases we also consid- patients, as well as studies of wild-type and mutant mice. We ered expression patterns, mutant phenotypes, and subcellular first designated the basic cellular process in which the gene is localization. In cases of “computed genes” predicted from the primarily involved, e.g., cytoskeleton or chromosome struc- Drosophila genome sequence, the absence of experimental ture. We then identified the site of primary organ system func- data made the evaluation of ortholog status more difficult. tion, relative to MR: endocrine system, central nervous system, or neither. For those genes that directly impact central nervous system (CNS) development and/or function, we ascertained the tissue type (neuron, glia, or blood vessel) and the specific RESULTS AND DISCUSSION cellular process affected (e.g., cell identity or differentiation). We also considered whether MR caused by mutation of the The 282 mental retardation genes have been molecu- gene is secondary to toxicity or secondary to energy or fuel deficiency. larly identified: Analysis of OMIM and literature search 838 J. K. Inlow and L. L. Restifo

TABLE 1 OMIM mental retardation entries

No. of % of Category Description entries entries 1 Known gene 254 25.1 2 Candidate gene 55 5.4 3 Chromosomal region 98 9.7 4 Candidate chromosome 26 2.6 5 Not mapped 416 41.2 6 Chromosomal abnormality 9 0.9 7 No MR phenotype 149 14.8 8 Nonexistent disorder 3 0.3 Total: 1010 100 This table is based on analysis of a search done on February 21, 2002.

gene and allelic variants have been identified (this category includes OMIM entries for the MR disorders Figure 1.—Diagram of the identification of human mental as well as separate entries describing the genes them- retardation genes and their comparison to D. melanogaster selves). genes. The OMIM searches were performed on February 21, Category 2: The disorder has been mapped to one or 2002. The literature search was completed on September 30, more candidate genes in a chromosomal region (con- 2003. tiguous gene deletion syndromes, e.g., Prader-Willi, are in this category). results allows us to present a status report on the genetics Category 3: The disorder has been mapped to a chromo- of MR. From the 1010 OMIM “mental retardation” en- somal region. tries obtained on February 21, 2002, we found 204 hu- Category 4: The disorder has been mapped to a candi- man genes that cause MR either in isolation or as part date chromosome. of a syndrome. Through literature searches we found Category 5: The disorder has not yet been mapped to 45 additional MR genes whose OMIM entries did not a chromosome. contain the search phrase “mental retardation.” About Category 6: The disorder is caused by a gross chromo- a quarter of these “false-negative” entries contained the somal abnormality and no single gene determines the phrases “psychomotor retardation” and/or “develop- MR phenotype (Down syndrome is one example). mental delay.” To include disorders causing very mild Category 7: MR is not a phenotype of the disorder. MR, we also searched OMIM for entries containing “cog- Category 8: The disorder does not exist. nitive impairment” or “learning disability” but not “men- The number of OMIM entries in category 1 (“known tal retardation.” Most of these 38 entries describe adult- gene”), 254, is greater than the number of genes, 204, onset, progressive cognitive impairment disorders, but because of OMIM database redundancy (see materials literature review identified 4 of them as MR genes. Fi- and methods). The nearly 600 OMIM entries in catego- nally, literature searches between March 2002 and Sep- ries 2–5 represent MR disorders in which the causative tember 30, 2003 revealed 29 recently identified MR genes were unknown (see below). Of the 29 recently genes for a total of 282 human genes known to cause discovered MR genes, half had “advanced” from “candi- MR (Figure 1). On the basis of these and subsequent date gene” (1 gene), “chromosomal region” (9 genes), publications, we estimate that new MR genes are being or “unmapped” (5 genes) categories. Thirteen repre- identified at a rate of 1–2 per month. The appendix sent new loci that can cause a known disorder. One lists the 282 MR genes in alphabetical order by their (FKRP) causes a form of muscular dystrophy, not pre- gene symbols, along with their associated MR disorders, viously associated with MR, that had been in category 7. chromosomal locations, OMIM numbers, and other in- Entries in category 6 (“chromosomal abnormality”) formation explained below. As will be discussed in later describe bona fide MR disorders, but we have not consid- sections, the MR genes control an extraordinary range ered them further in this analysis because they appear of molecular and cellular functions. to involve many genes (e.g., Shapiro 1999). It remains We classified the 1010 OMIM “mental retardation” to be determined whether individual genes that contrib- entries, based on data available in spring 2002, ac- ute to MR in cases of aneuploidy or other chromosomal cording to the following scheme (Table 1): defects can mutate to an MR phenotype individually. Category 1: The disorder has been mapped to a specific The 149 OMIM entries in category 7 (“no MR pheno- Molecular Genetics of Mental Retardation 839 type”) represent false positives in which MR is not a Fourth, mutations in genes controlling thyroid devel- phenotype (see materials and methods). Most of opment or function rarely cause MR in industrialized these false-positive errors could be eliminated by the societies because of neonatal screening and treatment adoption of a controlled vocabulary for OMIM clinical for hypothyroidism (Gruters et al. 2002). Hence, while synopses, with the previously mentioned caveat that MR a dozen known genes have been associated with MR definitions vary. The three entries in category 8 (“non- secondary to hypothyroidism (appendix), mutations in existent disorders”) do not represent distinct clinical other similar genes may not have had the “opportunity” entities, and one was subsequently removed from the to reveal whether they would cause MR in untreated OMIM database. patients. Finally, syndromal MR genes for which the MR OMIM MR entries in categories 2–5 (Ta- phenotype has very low penetrance present a significant 600ف With ble 1), it is obvious that many more MR genes remain to ascertainment challenge. For example, eight DNA re- be identified—but how many? Some of these disorders, pair genes/disorders are associated with MR in a modest particularly those in categories 4 (“candidate chromo- fraction of patients. It seems likely that more such disor- some”) and 5 (“not mapped”), are likely to represent ders (e.g., the rarer Fanconi anemia complementation MR genes that are already known. This is because of groups) have MR as a bona fide phenotype, but, presum- both practical difficulties in mapping human pheno- ably because the phenotype depends on chance somatic types and the phenomenon of phenotypic divergence; mutations during brain development (Gilmore et al. i.e., different mutant alleles of the same gene cause 2000), it is difficult to confidently assign MR to their distinct MR disorders (e.g., different DKC1 mutations clinical descriptions. result in dyskeratosis congenita or Hoyeraal-Hreidars- Given all these considerations, predicting the true son syndrome). Similarly, novel MR genes that remain number of human MR genes is difficult. A complete and to be identified may each explain more than one disor- accurate count may be beyond the capacity of medical der, especially within the large unmapped group. science to determine directly. We believe that 282 repre- sents substantially less than half of the total. It is easy ف Hence, this set of OMIM entries is likely to represent Ͻ595 genes. to imagine that human MR genes could number 1000. X-linked mental retardation genes: On the other hand, what MR disorders might be To date, eight X-linked genes are known to cause exclusively nonspe- “missing” from our analysis? First, we know that some cific MR (MRX genes), and 31 X-linked genes cause genes, or their corresponding disorders, are present in exclusively syndromal forms of MR (Table 2). Nonspe- the OMIM database but fail to appear in MR-related cific MR has been the focus of much attention, in part search results because of inconsistent use of terminology because of the idea that genes with “pure” behavioral in the medical literature, curatorial errors, or differing phenotypes, unaccompanied by gross brain abnormali- opinions on what constitutes mental retardation (see ties or other organ system defects, may provide greater materials and methods). Second, MR mutations oc- insight into the molecular basis of cognition than the curring in small families likely represent a large number syndromal MR genes (Chelly 1999; Toniolo 2000). of genes not yet listed in OMIM. Some families never Indeed, several MRX genes figure prominently in Rho- reach the attention of medical genetics research teams. type G-protein pathways (ARHGEF6, GDI1, OPHN1, Small pedigrees represent significant challenges for gene PAK3, FGD1; Ramakers 2002) or are regulated by neu- mapping, even on the X chromosome (Ropers et al. ronal activity (PAK3, IL1RAPL1, RSK2, TM4SF2; Boda 2003). The X-Linked Mental Retardation Genes Update et al. 2002). However, with the discovery that mutations Site (http://xlmr.interfree.it/home.htm; Chiurazzi et of five MR genes can cause either nonspecific or syndro- al. 2001) lists 57 nonspecific MR families and 110 mal MR (Table 2), the distinction between the two cate- X-linked MR syndromes for which the genes remain gories may not be as meaningful as originally proposed elusive. However, only 80 OMIM entries described (see discussion in Frints et al. 2002). X-linked MR disorders (syndromes and nonspecific) for For RSK2 (RPS6KA3), the phenotype difference is which genes have not been identified (Table 1, X-linked explained by allele type and severity. The R383W mu- entries in categories 2–4). tation that causes MRX19 is a partial loss-of-function A third “missing” or underrecognized category is com- allele, encoding a protein with 20% of wild-type kinase posed of essential genes of which most deleterious muta- activity (Merienne et al. 1999). In contrast, null mu- tions cause early prenatal lethality and only exceptional tations of RSK2 cause Coffin-Lowry syndrome with alleles with specific molecular consequences permit via- prominent skeletal and connective tissue involvement bility along with an MR phenotype. In genetic model (Hanauer and Young 2002). For several genes, the systems, complementation testing can easily show that a structure-function relationships are inferred but not di- viable “memory mutation” is allelic to mutations causing rectly demonstrated. The T1621M mutation of ATRX early death with profound neuroanatomical defects (also known as XH2 or XNP) causes nonspecific MR (e.g., Pinto et al. 1999), but comparable mapping stud- in the mild-to-moderate range (Yntema et al. 2002). ies are much more difficult in humans. Although residue 1621 is within the highly conserved 840 J. K. Inlow and L. L. Restifo

TABLE 2 X-linked mental retardation genes

Type of MR No. of XLMR % of XLMR disorder genes genes Gene symbols (see also appendix) Nonspecific only 8 18.2 ARHGEF6, FACL4, FMR2, GDI1, IL1RAPL1, OPHN1, PAK3, TM4SF2 Syndromal only 31 70.5 All other X-linked genes in the appendix Both 5 11.4 ARX, ATRX, FGD1, MECP2, RSK2 Total 44 100 XLMR, X-linked mental retardation.

SNF2-related domain, it is not conserved, suggesting Chromosomal distribution of human mental retarda- that some alterations at that site are compatible with tion genes: Of the 282 human MR genes, 11 are encoded partial function of this nuclear protein involved in chro- by the mitochondrial genome. Figure 2A shows the matin structure and transcription regulation. Missense chromosomal distribution of the 271 nuclear MR genes mutations just 7 and 12 residues upstream, however, compared to the chromosomal distribution of all known cause a more severe, syndromal phenotype with hemato- and predicted human genes based on the human ge- of %4ف logic, skeletal, and genital defects (Gibbons et al. 1995), nome sequence (Venter et al. 2001). While suggesting greater disruption of ATRX function. A vari- known and predicted genes are on the X chromosome, -of the MR genes reside there—a fourfold over %16ف -ety of FGD1 mutations, most of which truncate the en coded putative Rho GEF, cause Aarskog-Scott syndrome, representation. In contrast, the distribution of MR which includes highly penetrant skeletal and genital genes among the autosomes roughly parallels their rela- anomalies but infrequent, and only mild, MR. In con- tive gene contents (Figure 2A). An even greater X-chro- trast, one particular missense mutation in a region of mosome overrepresentation is found among the MR unknown function, P312L, causes severe, fully penetrant disorders mapped to candidate loci (6-fold), chromo- nonspecific MR (Lebel et al. 2002). somal regions (14-fold), and chromosomes (15-fold), Genotype-phenotype relationships are even more which correspond to categories 2, 3, and 4, respectively, complex for MECP2 and ARX. Within and among Rett of Table 1. syndrome families, females with MECP2 mutations show It has been proposed that the human X chromosome great clinical heterogeneity, with X-inactivation patterns contains a disproportionately high density of genes for and mutation sites believed to explain the severity differ- cognitive ability (Lehrke 1972; Turner and Parting- ences (Cheadle et al. 2000; Hammer et al. 2002). In ton 1991). This proposal generated controversy as well addition, at least seven different missense mutations in as speculation concerning possible underlying evolution- MECP2, scattered over the length of the protein, cause ary mechanisms, including the intriguing suggestion nonspecific MR (Orrico et al. 2000; Couvert et al. that female mate selection for high male intelligence 2001); several of these are very close to sites of Rett- helped accelerate the rapid rise of human cognitive syndrome-causing missense mutations (Cheadle et al. abilities (Turner 1996; Zechner et al. 2001). The identi- 2000; Hammer et al. 2002). For ARX, identical muta- fication of numerous MRX genes and X-linked MR syn- tions, resulting in polyalanine tract expansion of this dromes (Chiurazzi et al. 2001) seemed to support the homeodomain protein, caused nonspecific MR in one proposal. Opponents, however, argued that all X-linked family, but distinct neurological syndromes (West or recessive mutations are simply easier to map and identify Partington or MR with hypsarrhythmia) in various other because their phenotypes are revealed in hemizygous families (Stromme et al. 2002). This suggests a major males (Morton 1992; Lubs 1999). Countering this view effect of genetic background on ARX phenotypes. Other is an OMIM-based analysis (Zechner et al. 2001) show- ARX mutations cause a unique lissencephaly syndrome ing a 7.2-fold X-chromosome bias for MR genes, whereas with abnormal genitalia (Kitamura et al. 2002). genes causing common morphological phenotypes Complex genotype-phenotype relationships are also (polydactyly, cleft palate, facial dysplasia, skeletal dyspla- a feature of some autosomal MR disorders (e.g., FGFR1, sia, and growth retardation) have, on average, only a GLI3, PEX1, PTEN, PTPN11). On the basis of X-linked 2.4-fold X-chromosome bias. [Zechner et al. (2001) did MR, it is possible that some alleles of the one known not take OMIM errors, such as false positives and nega- autosomal nonspecific MR gene (PRSS12; Molinari et tives, into consideration, but such errors may be compa- al. 2002) will be found to cause a syndromal MR pheno- rable across phenotypes.] type. Conversely, autosomal genes presently known to To take this question one step further, we asked cause MR syndromes may be able to mutate to a nonspe- whether the apparent X-chromosome overrepresenta- cific MR phenotype. tion among the molecularly identified human MR genes Molecular Genetics of Mental Retardation 841

(Figure 2A) would disappear if we accounted for the plausible possibility that numerous autosomal loci are “hiding” among the unmapped MR genes (represented by the OMIM entries in category 5, Table 1). We at- tempted to overcome the ascertainment bias that favors identification of X-linked genes by making simplifying assumptions that maximize the estimate of autosomal MR genes and minimize the estimate of X-linked MR genes. First, we assumed that one OMIM entry equals one gene. Second, for the unmapped MR disorders (category 5, Table 1), we assumed that each represents a different, novel autosomal gene and that these are distributed in proportion to the overall gene distribu- tion on those chromosomes (Venter et al. 2001). Third, for those disorders whose genes map to chromosomal regions and candidate chromosomes (categories 3 and 4, Table 1), we assumed that there will be no new X-linked genes, i.e., that each potential X-linked gene is identical to an X-linked gene already known to cause MR. However, all candidate genes (category 2, Table 1), including the X-linked genes, were assumed to be new MR genes. Even when these very conservative (i.e., biased toward autosomal) assumptions are used to estimate the chro- mosomal distribution of the unknown MR genes, a 1.9- fold overrepresentation of MR genes on the X chromo- some remains (Figure 2B). This result supports the hypothesis that the X chromosome contains a dispro- portionately high density of genes influencing cognitive ability. One caveat is the possibility discussed above that many autosomal MR genes may be so rare or difficult to study that they never appear in the medical literature and, hence, in OMIM. We also agree with the suggestion of Lubs (1999) that resolution of this issue would be enhanced by analyzing genome-wide brain expression data and by searching for allelic variation in single genes responsible for the high end of the intelligence spec- trum. D. melanogaster homologs of human mental retarda- tion genes: We found that 87% of known MR genes (246/282) have at least one Drosophila homolog with ϫ Ϫ10 Figure 2.—Chromosomal distribution of human mental a BLASTP E-value of 1 10 or better (Figure 1; retardation genes and D. melanogaster orthologs. (A) The chro- appendix). Similarly, Reiter et al. (2001) found that human disease genes, representing all 1400ف mosomal distribution of the 271 molecularly identified nu- 75% of clear MR genes is compared to the chromosomal distribution major disease categories, have Drosophila homologs at of all nuclear, protein-coding human genes based on human genome sequence analysis (Venter et al. 2001). Note the this level of sequence similarity. More important, 76% striking overrepresentation of X-linked MR genes. (B) The (213) of the MR genes, including syndromal and non- predicted chromosomal distribution of known and potential syndromal types, have at least one Drosophila ortholog MR genes based on maximizing the assignment of genes to (see materials and methods and appendix). In fact, autosomes (see results and discussion), compared to all a handful of the human genes were named for their nuclear human genes as in A. The X-chromosome overrepre- sentation has been reduced, but remains almost twofold. (C) Drosophila orthologs, in most cases prior to their identi- The chromosomal distribution of the Drosophila MR gene fication as MR genes (ASPM: abnormal spindle-like, micro- orthologs is compared to the chromosomal distribution of cephaly-associated; EMX2: homolog 2 of empty spiracles; all nuclear, protein-coding Drosophila genes on the basis of PTCH: homolog of patched; PTCH2: homolog 2 of patched; Drosophila genome sequence analysis (Adams et al. 2000; see SHH: sonic hedgehog; SIX3: homolog 3 of sine oculis). FlyBase at http://flybase.bio.indiana.edu/ for Release 3). Dro- sophila homologs of human MR genes that are not orthologs The appendix lists the Drosophila homologs and or- were not included in this analysis. thologs of the MR genes, their FlyBase accession num- 842 J. K. Inlow and L. L. Restifo bers, and the BLASTP E-values (see also Figure 1 for the GO database (Figure 3; appendix; see materials overview). As discussed below, several dozen Drosophila and methods). The MR genes are distributed over a orthologs (designated “¶” in the appendix) are prime broad range of functions, indicating that disruption of candidates for cellular and molecular study of MR. Sev- any of a wide array of molecular processes can impair enteen MR genes (6%; designated with asterisk) have brain function so as to cause MR. Several categories are one or more homolog(s) that may be orthologs, but it prominently represented, such as enzymes (143 genes; is not possible to make a determination on the basis of 51%), mediators of signal transduction (32 genes; 12%) sequence analysis in the absence of experimental data. and transcription regulation (19 genes; 7%), binding Another 16 MR genes (6%; in brackets) have one or proteins (23 genes; 8%), and transporters (21 genes; more Drosophila homolog(s) that are not orthologs on 8%). Enzymes, especially those expressed in accessible the basis of reverse BLAST results or other sequence peripheral tissues, make gene identification easier than analysis (see materials and methods). There are 36 that for many other proteins, so their relative represen- MR genes (13%) with no Drosophila homolog, al- tation may decline as new MR genes are discovered. though this number may decline as final gene identifi- Other categories with smaller numbers of MR genes cation for the Drosophila genome is completed. include cell adhesion molecule, structural molecule, Some of the Drosophila genes are functional or- motor protein, tRNAs, apoptosis regulator, chaperone, ف thologs of human MR genes on the basis of experimen- and enzyme regulator. GO classifies 9% of the MR tal data. For instance, mutations of dfmr1, the Drosoph- genes (25) in the “unknown function” category, but ila ortholog of fragile X mental retardation 1 (FMR1; Wan published data suggest functions for all but 10 of them et al. 2000), cause specific disruptions of neuronal mor- (see appendix). phology (Zhang et al. 2001; Morales et al. 2002; Lee Within the GO molecular-function ontology, top-level et al. 2003; C. Michel, R. Kraft, B. Hassan and L. categories include fundamental molecular functions Restifo, unpublished results) and behavioral defects (e.g., binding activity, of which there are many subcate- (Dockendorff et al. 2002; Inoue et al. 2002). Genetic gories), as well as others related to a specific cellular and biochemical data suggest that Drosophila dFMR1 process (e.g., cell adhesion molecule), and in many is a regulator of translation (Zhang et al. 2001; Ishizuka cases, genes could be assigned to more than one. This makes classification, analysis, and comparison to other et al. 2002), as has been shown for mammalian FMRP sets of genes somewhat difficult. We did not classify any (Kaytor and Orr 2001; Laggerbauer et al. 2001; Maz- MR gene products as “defense/immunity proteins,” but roui et al. 2002; Zalfa et al. 2003). Although learning IKBKG encodes a subunit of a signal transducer (our phenotypes of dfmr1 mutant flies have not yet been category choice) that regulates NF-␬B in the immune reported, four of the fruit fly MR gene orthologs are and inflammatory response pathway (Wallach et al. “learning and memory genes” on the basis of behavioral 2002). We also did not use the “translation regulator” data: G protein s␣60A (Connolly et al. 1996), the or- category, but EIF2AK3 encodes a kinase (our category tholog of GNAS; Neurofibromin 1 (Guo et al. 2000), the choice) that indirectly regulates translation by phos- ortholog of NF1; cheerio (see Dubnau et al. 2003, online phorylating eukaryotic translation initiation factor-2 supplement), the ortholog of FLNA; and S6kII or igno- (Ma et al. 2002). Similarly, we classified FMR1 as “RNA rant (G. Putz,T.Zars, and M. Heisenberg, personal binding,” but considerable data demonstrate that it reg- communication), the ortholog of RSK2. Additional Dro- ulates translation (Jin and Warren 2003). In addition, sophila learning and memory genes have been pro- we could have classified some genes in the “protein posed as candidates for MR disorders that are not yet stabilization” (e.g., PPGB), cytoskeletal regulator (e.g., mapped (Morley and Montgomery 2001). TBCE), or “protein tagging” (e.g., UBE3A) categories. The Drosophila orthologs of the human MR genes However, anticoagulant, antifreeze, antioxidant, chap- do not have a skewed chromosomal distribution (Figure erone regulator, nutrient reservoir, and toxin are top- 2C). Approximately 16% of all fly genes and 16% of level categories in which none of the 282 MR genes MR gene orthologs are on the X chromosome. Of the could be placed. first two dozen Drosophila “learning and memory Figure 3 indicates the Drosophila-homolog status of genes” identified, almost 50% are X-linked (reviewed in the MR genes in each molecular-function category. The Dubnau and Tully 1998; Morley and Montgomery 213 MR genes with Drosophila ortholog(s) (solid bars) 2001). However, the recent isolation of 60 new auto- are distributed among the GO categories in roughly somal memory genes (Dubnau et al. 2003) indicates the same pattern as that of all the MR genes, with two that the older results reflect the previous tendency to exceptions. More than half of the “receptor binding” design X-chromosome screens for behavioral and genes (4 of 7) and 36% (9 of 25) of the “unknown neuroanatomical phenotypes. function” MR genes have no Drosophila homolog. Molecular functions of mental retardation genes: Biological functions of mental retardation genes: We Each of the 282 MR genes was classified in a single devised a “biological function(s)” classification scheme molecular-function category, primarily on the basis of for the 282 MR genes that considers both cellular- and Molecular Genetics of Mental Retardation 843

Figure 3.—Molecular function classification of mental retardation genes. Genes were classified on the basis of GO categories (see materials and methods). In cases where the top-level parent terms include large numbers of genes (signal transduction, binding, transcription regulation, enzyme), we show the distribution of genes among the children terms. For many of the genes that have not yet been classified by the GO Con- sortium, we used information from the literature to assign them to a GO term. For some of the genes designated “unknown function” by GO, we were able to assign provisional functions on the basis of published literature (see appendix), but these genes are included in the “unknown func- tion” category of this figure. As indicated by the boxed legend, each bar indicates classification of the human MR genes based on the degree of similarity to Drosophila genes.

systems-level perspectives (Figure 4; appendix; see ma- The major signaling pathways are represented among terials and methods). The basic cellular processes con- the MR genes, including those regulated by Sonic trolled by MR genes take place in the nucleus, in the Hedgehog (e.g., SHH), the TGF-␤ family of growth fac- cytoplasm (including within organelles), and at the in- tors (e.g., GPC3), Notch (e.g., JAG1), and calcium (e.g., terface among cells, cell compartments, and the extra- ATP2A2). MR-related signaling cascades are mediated cellular milieu. In the nucleus, MR genes affect chromo- by diverse cell surface proteins, such as integrins (e.g., some structure (e.g., DNMT3B), DNA repair (e.g., NBS1), ITGA7), G protein-coupled receptors (e.g., AGTR2), re- basal and regulated transcription (e.g., ERCC2 and SIX3, ceptor tyrosine kinases (e.g., NTRK1), and intracellular respectively), as well as rRNA processing (e.g., DKC1). proteins, including small G proteins (e.g., GDI1), hetero- In the cytoplasm, many MR genes have metabolic trimeric G proteins (e.g., GNAS), and phosphatidylinosi- functions (see also Kahler and Fahey 2003), involving tol (e.g., PTEN). Moreover, genes in a common pathway a wide range of pathways [citric acid cycle (e.g., FH), can share MR as a phenotype. SHH (Ming et al. 1998), gluconeogenesis (e.g., GK), glycolysis (e.g., PDHA1), oxi- through its receptors encoded by PTCH and PTCH2, dation (e.g., the PEX genes), oxidative phosphorylation regulates GLI3, some of whose targets are also regulated (e.g., MTCO1), urea cycle (e.g., OTC), and general cell by GPC3. integrity (e.g., GSS)] and biologically critical com- MR genes also control communication and transport pounds [amine (e.g., MAOA), amino acid (e.g., OAT), across cell and organelle membranes. These include carbohydrate (e.g., GALE), cholesterol (e.g., SC5DL), cation-chloride cotransporters (SLC12A1, SLC12A6) creatine (e.g., GATM), fatty acid (e.g., ALDH3A2), heme that may be critical for inhibitory neurotransmission (e.g., PPOX), lipid (e.g., DIA), methionine (e.g., (Payne et al. 2003). The transmembrane linkage (ITGA7, MAT1A), purine (e.g., HPRT), pyrimidine (e.g., DPYD), TM4SF2) between the extracellular matrix (LAMA2) and and cofactors (e.g., TC2)]. MR genes involved in macro- the cytoskeleton is strongly implicated in MR, as is cell molecular synthesis and modification include those re- adhesion (L1CAM). quired for mitochondrial translation (e.g., MTTK), The overlap between MR and muscle disease is strik- translation regulation (e.g., FMR1), protein folding (e.g., ing and appears to arise from at least three distinct BBS6), protein stability (e.g., PPGB), protein glycosyla- mechanisms: reduced membrane/cytoskeletal stability tion (e.g., PPM2), and lipid synthesis (FACL4). Macro- (DMD, ITGA7, LAMA2); glycosylation defects associated molecular degradation in lysosomal (e.g., HEXA) and with abnormal neuronal migration (FCMD, FKRP, proteasomal (e.g., UBE3A) pathways is also commonly LARGE, POMGNT1, POMT1); and mitochondrial dys- disrupted by mutations in MR genes. MR genes have function (MTCO3 and many others). The biological major effects on the cytoskeleton, including its actin basis of myotonic dystrophy (DM1) is unknown. (e.g., FLNA), microtubule (e.g., DCX), and intermediate An integrative view of MR biology: The hereditary filament (e.g., GFAP) components. MR disorders can be approached from two somewhat 844 J. K. Inlow and L. L. Restifo

Figure 4.—Biological functions that underlie mental retardation. Diagram of a mammalian cor- tical neuron and associated structures in the cen- tral nervous system. The physiological connection to the endocrine system via the bloodstream is indicated in the bottom left. Sizes are not to scale. Solid triangles represent hormone molecules. Each of the unboxed terms, in roman type, is a biological function regulated by one or more MR genes or results from mutation of an MR gene (see appendix).

independent perspectives: (i) where the genes are ex- pancreas to regulate ATP-dependent, exocytotic insulin pressed and function and (ii) the relationship between secretion. Mutations in either gene cause excess insu- the mutation and pathogenesis of the MR phenotype. lin release and hypoglycemia which, if inadequately Genes may act selectively within the brain (“intrinsic treated, disrupts brain development and function due or selective function”) or primarily outside the CNS to systemic fuel deficiency (Vannucci and Vannucci (“extrinsic or generalized function”). MR may result 2001; Huopio et al. 2002). Similarly, the brain’s energy from fundamental cellular defects that impair many requirements make it very sensitive to genetic disrup- tissues (“generic effect”), with the brain sometimes hav- tions of mitochondrial function (Chow and Thorburn ing a higher sensitivity, or MR can result from selective 2000). Mutations in mitochondrial genes (MTATP6, impairment of unique features of brain development MTCO1, MTCO2, MTCO3, MTCYB, MTTE, MTTK, or physiology (“selective effect”). With the caveat that MTTL1, MTTS1) or in nuclear genes encoding mito- MR pathogenesis is incompletely understood and that chondrial proteins (BCS1L, SCO2, SURF1, TIMM8A) spatial expression data are limited, we consider exam- cause MR due to local energy (ATP) deficiency in neu- ples of MR genes in these major categories. rons and glia (Servidei 2001). Extrinsic or generalized function/generic effect: ABCC8 Extrinsic or generalized function/selective effect: In the en- (SUR1) and KCNJ11 gene products work together in the docrine system, locally synthesized hormones enter the Molecular Genetics of Mental Retardation 845 circulation and affect distant organs. MR genes include aly (“smooth brain”) due to mutations in LIS1, DCX, several tissue-specific regulators of thyroid gland devel- and RELN, as well as ARX (some alleles) and FLNA opment (TTF2, PAX8) or thyroid hormone synthesis (Olson and Walsh 2002). Agenesis (partial or com- (DUOX2, TG, TPO; Kopp 2002). Mutations in these plete) and dysgenesis of the interhemispheric corpus cause congenital hypothyroidism, and mutations in a callosum (Davila-Gutierrez 2002) are relatively com- receptor (THRB) cause thyroid hormone resistance. In mon MR-associated phenotypes (e.g., CXORF5, GLI3, either case, brain cells cannot initiate the transcriptional OCRL, SLC12A6, TSC1, TSC2) and may be isolated or cascade that controls neuronal size, migration, and den- accompany holoprosencephaly and other abnormali- dritic morphology, as well as oligodendrocyte differenti- ties. ation (Thompson and Potter 2000). Hence, neuronal A handful of MR genes and their primary cellular circuitry and myelination are disrupted. phenotypes are glia specific. Dominant missense muta- Many metabolic MR genes fall into this category as tions in GFAP cause Alexander disease due to astrocytic well. AASS is expressed in most tissues and encodes a accumulation of abnormal intermediate filaments and key enzyme in lysine metabolism (Sacksteder et al. secondary demyelination (Johnson 2002). In contrast, 2000). In patients lacking AASS function, lysine accumu- PLP1 is expressed solely in oligodendrocytes and en- lates and inhibits arginase, causing excess circulating codes the most abundant CNS myelin protein. Myelin ammonia, which interferes with neuronal and glial func- integrity is very sensitive to PLP1 gene dosage, with du- tions (Felipo and Butterworth 2002). Similarly, PAH plications, deletions, and missense mutations all caus- is expressed mainly in nonneural tissues (Lichter- ing Pelizaeus-Merzbacher disease (Koeppen and Robi- Konecki et al. 1999), with mutations causing elevated taille 2002). circulating phenylalanine. This systemic toxin impairs At the other end of the spectrum are the many heredi- myelination, synaptogenesis (Bauman and Kemper tary MR disorders for which routine neuropathological 1982; Huttenlocher 2000), and possibly aminergic data are unavailable or fail to show consistent defects. neurotransmission (Surtees and Blau 2000). The lyso- Higher-resolution Golgi staining has revealed dendritic somal storage disorders, which cause macromolecules abnormalities of cortical neurons in fragile-X (FMR1; to accumulate in many tissues, may also belong to this Irwin et al. 2000) and Rett syndromes (MECP2; Arm- category. Most represent degradative enzyme deficien- strong 2001) and possibly in Rubinstein-Taybi syn- cies, but some of the genes encode transport, stabilizer, drome (CREBBP; Kaufmann and Moser 2000). All or activator proteins (Wisniewski et al. 2001). They are three likely result from misregulated gene expression classified by the compounds that accumulate in lyso- in the brain, but which target genes are responsible for somes, such as sphingolipidoses (e.g., ARSA), neuronal the dendritic defects remain to be determined. ceroid lipofuscinoses (e.g., CLN1), glyoproteinoses (e.g., For MR disorders with no known anatomical lesions, PPGB), and mucolipidoses (e.g., NEU1). The traditional such as nonsyndromal MRX, gene function in the CNS view that the progressive brain phenotypes result “sim- is inferred from molecular analyses. For example, GDI1 ply” from local toxicity is countered by reports of specific (MRX41, MRX48; Bienvenu et al. 1998) encodes a neurodevelopmental defects (Walkley 1998; Alta- brain-specific regulator of Rab-type G proteins. One of rescu et al. 2002). its targets is believed to be Rab3A, which controls activ- Intrinsic function/selective effect: For genes with selective ity-dependent synaptic vesicle recruitment to axon ter- expression or function within the CNS, the conse- minals (Leenders et al. 2001). Given the structure-func- quences of mutations are also primarily CNS selective, tion relationships underlying developmental synaptic with variation in cell-type involvement and severity plasticity (Cohen-Cory 2002), it seems likely that neuro- (Pomeroy and Kim 2000). The coexistence of neuro- anatomical phenotypes for this and other MRX disor- pathology and cognitive deficits supports the view of ders will eventually be found. MR as a disorder of brain development or plasticity. At Regardless of the scheme used, many disorders defy one end of the spectrum are MR disorders with gross straightforward classification. For example, the role of brain malformations. Holoprosencephaly, a failure of homocysteine in CNS development and function the right and left brain halves to form distinct hemi- (Mattson and Shea 2003) belies the “metabolic” classi- spheres, results from mutations in genes controlling fication of the MR genes CBS, MTHFR, MTR, MTRR, cellular identity of forebrain neuronal precursors and TC2. The MR genes SC5DL and DHCR7 encode (PTCH, SHH, SIX3, TDGF1, TGIF, ZIC2; Wallis and enzymes in cholesterol biosynthesis, making them also Muenke 2000). Schizencephaly (“cleft brain”) is due to primarily “metabolic.” However, because Sonic Hedge- dominant missense mutations in EMX2, which encodes hog protein function is absolutely dependent on cova- a homeodomain-containing transcription factor (Faiella lent linkage to cholesterol (Ingham and McMahon et al. 1997). Abnormal neuronal migration in the rostral 2001), the enzymatic deficiencies may impair SHH sig- forebrain (the region of EMX2 expression) causes gross naling. It may be that, with sufficient research on molec- morphogenetic as well as more subtle lamination de- ular and cellular pathogenesis, few if any MR genes will fects. Neuronal migration defects also cause lissenceph- be considered “just metabolic.” 846 J. K. Inlow and L. L. Restifo ) f continued ( cking/post-translational fi nding lament organization; fi /Wnt signaling; NMJ fi ␤ processing structure/function growth wrapping by glia structure/function survival] path phototransduction pupariation Drosophila ortholog 9A Yes, N TGF- 1A Yes Molybdenum cofactor biosynthesis 96E UP41AC [Transcription regulation; chromatin None60C [Microtubule cytoskeleton; Yes neurite rRNA processing; cell and organismal 38C NP [Rho pathway; actin cytoskeleton; 96A60A Yes, N Yes Spindle formation; cytokinesis Protein traf 92A NP70C Yes, N [Plasma membrane-cytoskeleton Glial cell migration 90E Yes, N Axon outgrowth, guidance, and 89E Yes,85F N Yes, Actin 85E N NP Translation regulation; neuron [Transcription regulation] 44F Yes11E Yes, N Glucose metabolism; [neuronal Tissue adhesion; cell migration; axon 60A Yes, N66E Yes, Locomotor N behavior; learning; Wnt pathway; cell cycle; neurogenesis 30B Yes Rab GTPase binding; growth; 102A Yes, N Hh pathway; transcription; neuron location Mutants Biological function in Drosophila D. melanogaster e 60A ␣ 60A 60B XNP nejire CG17528 Nucleolar protein rtGEF abnormal spindle Calcium ATPase dystrophin breathless heartless cheerio dfmr1 CG16899 pgi mew G protein s cinnamon dally Gene name GDI cubitus interruptus d Yes/? TABLE 3 mutant/MR c GlyR and Yes/yes ↓ cation Yes/? fi neural tube apoptosis; Yes/? Mammalian brain Mouse Gene ↓ phenotype includes: arborization heterotopia, pachygyriaslow myelination outgrowth] obvious defects morphogenesis] white matter Human mental retardation genes: prime candidates for study in b c MR microcephaly; ACC structure] fi Human disease ciency type C GABA-R clustering fi nonspeci dystrophy dendrites; astrocytosis linkage] syndromedyspraxia ?immature areas heterotopia ACC; cerebellar hypoplasia long-term memory de osteodystrophy syndrome type I others abnormal DV pattern differentiation -Thalassemia/MR syndrome; Mild cerebral atrophy; None ␣ Apert and other ACC; abnormal limbic and Yes/? a (1) MRX46 Presumed to have no None (5) Rubinstein-Taybi syndrome ACC; decreased dendritic Yes/yes (3) Darier-White disease Unknown Yes/? (12) Developmental verbal Abnormal frontal lobe motor None (19) Congenital myopathy Cortical atrophy; abnormal None (4) (2) Primary microcephaly 5 Microcephaly None (11) Fragile X mental retardation Abnormal dendritic spines, Yes/yes (15) Albright hereditary Cerebral calci (7) Dyskeratosis congenita; HHS ACC; cerebellar hypoplasia; Yes/? (10) Periventricular nodular Periventricular heterotopia; None (16) Simpson-Golabi-Behmel Unknown Yes/? (8) Duchenne/Becker m. Neuron loss; abnormal Yes/yes (13) MRX41, MRX48 No obvious defects Yes/yes (14) Acrocallosal syndrome; ACC; (17) Molybdenum cofactor Cerebral atrophy; (6) X-linked lissencephaly Abnormal cortical lamination: Yes/yes (9) craniosynostosis syndromes pyramidal tract; heterotopia (18) Hemolytic anemia ?Loss of neurotrophic activity Yes/? -3 ATRX CREBBP DKC1 DCX DMD ASPM ARHGEF6 ATP2A2 FGFR-1,-2, FLNA GDI1 FMR1 FOXP2 ITGA7 GPI GPH GPC3 Human gene GLI3 GNAS Molecular Genetics of Mental Retardation 847 ) f continued ( nding fi nding nding fi fi dimerization] guidance neurogenesis memory path ?protein sorting] path Drosophila ortholog 2D Yes, N RTK pathways; cell fate, migration, 2B NP [Inositol phosphate pathway; 7F Yes, N Neuron adhesion/morphology; axon 42A UP [Chaperone; tubulin folding and 44A29F NP Yes, N Induces Cell eye fate; development neurogenesis; axon 94E Yes, N Morphogen expression; patterning; 20A Yes, N [Signaling pathways]; learning and 31B Yes Cell size and proliferation; insulin 66F NP [Serine protease] 83E Yes, N Axon path 13E NP; R; N Axon stability 98B NP [Transcription regulation] 96F Yes, N Ras pathway; glial growth; learning/ 35A Yes52F Yes, N Cell migration32A and adhesion Neurogenesis; dendritogenesis; NP43D UP ?Embryonic CNS development Embryogenesis 97E Yes, N Notch pathway; cell fate; location Mutants Biological function in Drosophila e ) bromin 1 fi CG6256 CG7861 Optix SoxNeuro hedgehog S6kII corkscrew Pten Tequila Pak Graf Mes-4 EG:86E4.5 Neuro CG31721 didum wing blister Lissencephaly-1 neuroglian Serrate Gene name d TABLE 3 (Continued) mutant/MR c cerebellum ↓ neuron size pathway ↑ Mammalian brain Mouse Gene phenotype includes: fate failure defects white matter; glial tumors memory defects; cortical atrophyabnormal dendritic spines ( and neuronal patterning neurogenesis Cortical lamination: Yes/yes ↓ b ) c MR defects fi bromatosis Megencephaly; abnormal Yes/yes appendix Human disease fi ciency n-Lowry syndrome; ACC; dilated ventricles Yes/yes fi fi (see de MRX19 syndrome LEOPARD syndrome Bannayan-Zonana lamination; nonspeci syndromesyndrome ventricles dystrophyperiventricularheterotopia white pachy/agyria, matter; heterotopia axonal transport SPG1 a (33) Noonan syndrome; Unknown Yes/? (25) Elejalde syndrome Cerebellar hypoplasia; Yes/yes (22) Congenital muscular Abnormal lamination and Yes/yes (29) MRX60 Presumed to have no obvious None (21) MASA syndrome; HSAS; ACC; hydrocephalus Yes/yes (31) Autosomal recessive Presumed to have no obvious None (28) Lowe oculocerebrorenal ACC; abnormal white matter Yes/no (32) Cowden syndrome; Megencephaly; abnormal Yes/yes (38) HRD syndrome Unknown; ?axon degeneration Yes/yes (24) Opitz syndrome type I ACC and other midline None (30) MRX 30; MRX47 No obvious defects None (27) Nijmegen breakage ACC; polygyria; dilated None (37) MR with growth hormone Unknown None (34) Cof (20) Alagille syndrome Abnormal vessels (moyamoya) Yes/? (35) Holoprosencephaly 3 Holoprosencephaly; ventral Yes/yes (36) Holoprosencephaly 2 Holoprosencephaly None (23) Lissencephaly; (26) Neuro TBCE SOX3 SIX3 SHH RSK2 PTPN11 PTEN PRSS12 PAK3 OPHN1 OCRL NSD1 MYO5A NF1 LAMA2 MID1 LIS1 L1CAM JAG1 Human gene 848 J. K. Inlow and L. L. Restifo a et et et et f and and nding (2002); fi (1999); Krantz Fortini Odent Overton Billuart Bienvenu Akaboshi Alonso - Smith Oldham - 1997); (22) ally; yes/no, Kugler and et al. et al. Takagishi ested but not (1999); elements; None, known function. (2002); Garcia P Periz (2003); Chyb Bieber ( (2002); Clayton et al. (2000); (2003); (7) (1998); (29) et al. (1998); (13) et al. and et al. (1992); et al. (1999); et al. (1996); Li et al. Dockendorff et al. Luo Hall et al. Lin et al. et al. Sanal (1998); (40) Buescher [interacts with Hh pathway] Woolfenden ybase.bio.indiana.edu/ for details). (1998); (2001); fl Khadem / - Friocourt et al. (2000); Klambt et al. et al. personal communication); (35) Jacobsen (2002); Connolly et al. . (1999); (18) . (2003); (28) Canal Vargha (2002); (25) 1998); (20) et al. (1999); Marsh Zhang Drosophila ortholog et al et al (2000); (6) 2000); et al. Alonso et al. (2001); (3) - Chiba ( . (2001); et al. Heisenberg ( 82E Yes Tissue morphogenesis; 76F Yes,68B N UP Cell size; cell cycle; axon path [Selective protein degradation] (2000); Wittle location Mutants Biological function in Drosophila et al. and et al Brody Douglas Bueno Laumonnier Garcia (2002); (32) - -element insertion in the gene; NP, nearby et al. Marek P and M. Trembath ( e Tapon . (2001); et al. Hoang (2000); and 2001); Passos Irwin Zars 2002); et al Wakefield (2000); (27) et al. ,T. 2000); (37) 2001); (unpublished results); (12) (2002); Reiss Aldred odd paired CG6190 gigas Gene name et al. Molinari Cox Putz (2002); Gartner ( 2000); (9) d et al. Takaesu ( Guo Restifo . (2003); (11) et al. and Gehring ( and 1995). . Takashima ( et al and 1998); (15) (2002); G. (1999); (17) Bond TABLE 3 Roberts ( and L. (1999); (31) (2000); (24) Pegoraro and . (2001); (Continued) mutant/MR Weller et al. and appendix Newfeld et al. et al Sakonju ( et al. et al. Dubnau Kunes ( Seimiya ed only by genome sequencing projects (see FlyBase at http:/ 2002); c fi and Liu 1997); (2) B. Hassan 1998); and Hing Yager Tsuda , Mizuguchi Jacquot Greener (1999); (2000); (1990); (21) Brown ( (2002); 2002); et al. Cimbora Huang (1998); (1995); et al. and et al. Manseau ( dendritic arbors (2002); Gagliesi ( Li ↓ et al. ; abnormal gyral Yes/yes ” et al. et al. have been identi and (2002); (39) and (1996); (34) ” et al. (2000); Mammalian brain Mouse Gene (2002); Bokel phenotype includes: Gutmann ( EG (1998); Fleming Pasquier “ et al. nodules; astrocytomas neurulation pattern; et al. Allen et al. Atrophy et al. Cardoso “ C. Michel, R. Kraft Nakato and Werner and et al. Cantani ” Anderson (1995); Nagai Martin Elson CG Fox Perkins “ . (2000); (2002); Lynch (2000); b 2001); (36) . (2001); et al. xes et al fi (1999); (23) 2000); (5) et al. et al et al. (2001); (2002); Gu (2003); Li (1999); (8) -values. et al. et al. E et al. (1997); (10) et al. . (2001); (14) Higgs ( (1998); (26) McMahon ( et al. Bienvenu (2001); elements known to be nearby; R, function assessed by double-stranded RNA interference; N, behavioral and/or neuroanatomical phenotype Morales Kutsche Human disease et al P et al. and et al. and Martin Brown et al. Parvari for alternate gene symbols. Numbers in parentheses following individual genes refer to representative references from the mammalian and Drosophil (2001); (16) Musante (2002); for BLASTP Tsai Ricard Giordano a Gibbons et al. (2001); Ingham Shishido 2000); see FlyBase ID FBgn0003074; (19) MacIver et al. appendix (40) Angelman syndrome 2003); (41) et al. (39) Tuberous sclerosis 2 Cortical tubers; subcortical Yes/yes (1998); (41) Holoprosencephaly 5 Holoprosencephaly; defective Yes/yes (1998, 2001); (30) (2002); (38) appendix . (1998); . (2000); See Yes/yes, mouse mutant displays a neurological or behavioral phenotype relevant to MR; yes/?, mouse mutant has not yet been characterized neurologic Additional disorders may be caused by mutation of these genes; see the Based on neuropathology, neurophysiology, and/or brain imaging of human patients. In some cases, data from mouse mutants were also considered. The Drosophila genes with pre Biological functions in brackets are inferred from molecular data (including gene expression and biochemistry) or sequence homology to proteins of (1999); (2002); (33) (1996); ACC, agenesis, dysgenesis, or hypoplasia of the corpus callosum; DV, dorsal-ventral; UP, uncharacterized a b c d e f . (2000); 1999); (4) UBE3A ZIC2 no mutants andresults no from disruptionconclusively by demonstrated. mutation or RNAi; Hh, hedgehog; NMJ, neuromuscular junction; RTK, receptor tyrosine kinase. ?, precedes phenotypes sugg See TSC2 et al genetics literature: (1) mouse mutant has no known neurological phenotype; none, no mouse mutant. All others are based on mutant phenotypes. Human gene al ( Wolfgang Lakomek ( Ishizuka et al. Jones et al al. et al. Laan ( al. et al. al. Molecular Genetics of Mental Retardation 849

The role of D. melanogaster in MR research: In terms a ligand of Notch (the Drosophila ligand is Serrate). of primary amino acid sequence and protein-domain orga- The biological relevance of genetic interactions in hu- nization, the degree of MR gene conservation between man MR is well demonstrated by some of the Bardet- humans and Drosophila is remarkable (Figure 1; appen- Biedl syndromes (BBS2 and BBS6; see appendix)in dix). Not only individual genes but also whole pathways which clinical manifestations result from “triallelic in- -million years of evolu- heritance,” homozygosity at one locus and heterozygos 700ف have been retained through tion. These include protein glycosylation (ALG3, ALG6, ity at another (Katsanis et al. 2001). Genetic interaction B4GALT1, DPM1, FUCT1, GCS1, MGAT2, MPDU1, PMI, tests in Drosophila could help clarify the functional PPM2), as well as signaling pathways, notably the Hedge- relevance of the physical interaction between mamma- hog pathway (SHH, PTCH, PTCH2, GLI3, GPC3) and those lian ZIC2 and GLI3 proteins (Koyabu et al. 2001). mediated by small G proteins (ARHGEF6, GDI1, OPHN1, The number of MR genes is very large, but they may be PAK3, FGD1, GPH, RSK2, and others). involved in a relatively small number of interconnected Given this remarkable conservation of MR genes, we pathways. If so, a modest number of pharmacological propose that Drosophila genetics can be used in a sys- treatment strategies might be effective for many MR tematic manner to study MR. We have selected 42 fly patients. In fact, some types of acquired MR might bene- genes (the orthologs of 43 human MR genes) as “prime fit from the same drugs. Diagnoses of hereditary MR are candidates” for such analyses (Table 3). These genes typically made early in life at a time when developmental most likely act selectively within the brain during devel- brain plasticity provides an opportunity for therapeutic opment to establish the anatomical and physiological intervention. The widespread functional conservation substrates for experience-dependent plasticity. The ma- of MR genes in Drosophila indicates that this genetic jority of prime-candidate orthologs currently have fly model system could play a critical role in the discovery mutants available (about the same fraction as have of novel treatment strategies for MR. mouse mutants available) and the rest can be mutagen- The authors thank Brian Blood for recent literature searches and ized through the mobilization of nearby transposable BLAST analyses to update the list of human MR genes and their elements or studied using RNA interference methods Drosophila homologs. The authors are grateful to colleagues David (Adams and Sekelsky 2002). About half are already Mount for advice on bioinformatics methods, Terrill Yuhas and Nirav known to have neural phenotypes, behavioral or ana- Merchant for computer support, Charles Hedgecock for assistance with computer graphics, and John Meaney and Robert Erickson for tomical, in Drosophila (Table 3 and references therein). helpful discussions about human genetic disease. This work was The anatomical defects involve neurons (e.g., cubitus funded by the National Institutes of Health (grant no. P01 NS028495). interruptus), glia (e.g., Neurofibromin 1), and neural pre- cursor cells (e.g., division abnormally delayed) and result Note added in proof: Evaluation of recently updated OMIM entries from problems with proliferation (e.g., hedgehog), migra- revealed three more MR genes whose molecular identifications were published prior to September 30, 2003. 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Hawley Molecular Genetics of Mental Retardation 855 ) h 45 18 83 14 128 300 105 179 147 151 155 300 Ϫ Ϫ Ϫ Ϫ -value Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ E continued ( g no. 0022709 0038467 0033431 0037661 0025687 , 0027572 f (&) , 0004622 , others] 0032026 (&) 0039349 (&) 0037138 (&) 0036927 (&) 0010548 homolog(s) kinase-1 CG10474 deaminase Takr99D CG7627 Adenylate CG4685 Aldh-III CG7145 CG3590 CG1827, Adenosine BcDNA:GH07485 CG7433 BEST:CK02318 e Њ uid others] fl local toxicity local toxicity others systemic fuel systemic toxicity Њ Њ Њ Њ ciency local toxicity; fi Њ homologs MR cause unknown balance; CNS development/ function (GPCR): cause unknown development/ function MR 2 (neuron) (glycoprotein): ?neuromodulation systemic toxicity (glia: myelin) neurotransmission (GABA) Biological function(s) d D. melanogaster Molecular- APPENDIX no. category c ciency 2 ciency homeostasis): MR fi fi Human mental retardation genes and Clinical disorder to AK1 de autism synthesis): ?MR 2 immunode infancy de b Gene name arm 5A1 metabolism (GABA) 4A1 type 2 3A2 syndrome synthesis): CNS aminotransferase metabolism function: oxidase 1 adrenoleukodystrophy MR 2 semialdehyde synthase MR 2 -Aminoadipic 7q Hyperlysinemia 605113 Oxidoreductase Metabolic (amino acid): Aldehyde dehydrogenase 6p Inborn error of GABA 271980 Oxidoreductase Neurotransmission Adenylate kinase 1 9q Hemolytic anemia due 103000 Kinase Metabolic (purine Aldehyde dehydrogenase 17p Sjogren-Larsson 270200 Oxidoreductase Metabolic (fatty acid Aldehyde dehydrogenase 1p Hyperprolinemia type II 606811 Oxidoreductase Metabolic (amino acid): Angiotensin II receptor Xq X-linked MR 300034 Receptor Signaling pathway [ Adenylosuccinate lyase 22qAspartylglucosaminidase Succinylpurinemic 4q Aspartylglucosaminuria 103050 208400 Lyase Hydrolase Lysosomal pathway Metabolic (purine Adenosine deaminase 20q ADA-severe combined 102700 Hydrolase Metabolic (purine): ?MR ATP-binding cassette, 11p Hyperinsulinemic 600509 Receptor Endocrine (pancreas): [ Acyl-coenzyme A 17q Pseudoneonatal 264470 Oxidoreductase Metabolic (fatty acid): 4-Aminobutyrate 16p Inborn error of GABA 137150 Transferase CNS development/ ␣ ) subfamily C, member 8 hypoglycemia of MR 2 a ••• SUR1 ( ALDH5A1 AK1 ALDH3A2 ALDH4A1 AGTR2 ADSL AGA ADA ABCC8 ACOX1 ABAT AASS Genesymbol Chr. OMIM function GO Drosophila FlyBase BLASTP 856 J. K. Inlow and L. L. Restifo ) h 29 23 55 90 76 98 60 104 131 100 Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ -value Ϫ Ϫ Ϫ E continued ( g —— no. 0023489 0011297 0000064 0032287 0032234 0037743 0023535 f , ) * ) 0015803 , 0052191 ¶ CG5432 (&) 0035401 , (& homolog(s) homology 13 others ( of tid PvuII-PstI CG32191 lethal (2) neighbor CG6415 CG1291 CG5091 CG8412 arginase rtGEF Aldolase e Њ Њ cation cation cation cation fi fi fi fi neuro/glial systemic Њ Њ local toxicity (neuron) local toxicity (glia: myelin) development/ function plasticity development/ function development/ function development/ function MR 2 MR 2 toxicity (neurotransmission) toxicity Biological function(s) d Molecular- protein development/ APPENDIX (Continued) no. category c ciency integrity fi Clinical disorder lissencephaly migration others leukodystrophy (glycolipid): MR 2 glycosylation type Ii (glycosylation): CNS glycosylation type Id (glycosylation): CNS ALDOA de glycosylation type Icglycosylation type Ig (glycosylation): CNS (glycosylation): CNS b Gene name arm (ceramidase) amidohydrolase lipogranulomatosis (glycolipid): MR 2 homeobox, X-linked Partington syndrome; regulator function: neuronal Asparagine Linked Gene 2 Asparagine Linked Asparagine Linked Gene 6 Asparagine Linked Gene 12 Gene 3 -Acylsphingosine 8p Farber 228000 Hydrolase Lysosomal pathway None Aristaless-related Xp MRX36; West syndrome; 300382 Transcription CNS development/ Homolog of yeast 3q Congenital disorder of 601110 Transferase Protein modi Arylsulfatase A 22q Metachromatic 250100 Hydrolase Lysosomal pathway Homolog of yeast 9q Congenital disorder of 607905 Transferase Protein modi Homolog of yeastAminomethyltransferase 22q Congenital 3p disorder of Glycine encephalopathy 607144 238310 Transferase Transferase Protein modi Metabolic (amino acid): Homolog of yeast 1p Congenital disorder of 604566 Transferase Protein modi ArginaseRho guanine nucleotide Xq MRX46 6q Argininemia 300267 207800 Receptor Hydrolase Signaling pathway Metabolic (urea cycle): Aldolase A 16q Hemolytic anemia due to 103850 Lyase Metabolic: general cell ) ) exchange factor 6 signaling (integrin): neuronal a NOT65L PIXA ( ( ASAH N ARX ALG3 ARSA ALG2 ALG12 AMT ALG6 ARG1 ARHGEF6 ALDOA Genesymbol Chr. OMIM function GO Drosophila FlyBase BLASTP Molecular Genetics of Mental Retardation 857 ) h 73 62 60 30 54 300 300 121 300 106 300 Ϫ Ϫ Ϫ Ϫ Ϫ -value Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ E continued ( g —— —— no. 0035741 0000140 0026565 0032076 0004551 ) 0039396 * , 0027538 f ) ¶ ) (&) 0039258 ¶ (& ) 0039338 (&) 0030343 ¶ ,others( (& (&) 0004367 (& homolog(s) CG14517 spindle 60A CG11780 CG14825 BcDNA:GH13356 CG6111 mei-41 XNP abnormal BG:DS00004.14 CG9510 CG1886 Calcium ATPase at e local Њ Њ cation cation fi fi systemic toxicity systemic toxicity Њ Њ development/ function development/ function systemic toxicity development/ function toxicity (myelin) function: neurogenesis development/ function; MR 2 (calcium): cell adhesion (skin); MR cause unknown Biological function(s) d Molecular- function function APPENDIX (Continued) no. category c and transcription fi c Clinical disorder MR; others regulation syndrome function caciduria MR 2 -Thalassemia/MR 300032 Helicase Chromosome structure ␣ b - 12q Darier-White disease 108740 Transporter Signaling pathway ) ϩ -polypeptide occipital horn development/ (2 ␣ Gene name arm -transporting Xq Menkes syndrome; 300011 Transporter Metabolic: CNS ϩ 2 Galactosyltransferase 1 glycosylation type IId (glycosylation): CNS receptor 2 diabetes insipidus (GPCR): MR 2 RAD3-related microcephaly- synthetase (type I) MR 2 associated ATPase, transporting, slow-twitch -1,4- 5q Ehlers-Danlos syndrome, 604327 Transferase Protein modi -1,4- 9p Congenital disorder of 137060 Transferase Protein modi Bardet-Biedl syndrome 1 11q Bardet-Biedl syndrome 1 209901 Unknown Unknown Bardet-Biedl syndrome 2 16q Bardet-Biedl syndrome 2 606151 Unknown Unknown None ␤ ␤ Arginine vasopressin Xq X-linked nephrogenic 304800 Receptor Signaling pathway Ataxia-telangiectasia and 3q Seckel syndrome 601215 Kinase DNA repair: CNS X-linked helicase 2 Xq ATPase, Ca Abnormal spindle-like, 1q Primary microcephaly 5 605481 Protein binding CNS development/ Argininosuccinate 9q Classic citrullinemia 603470 Ligase Metabolic (urea cycle): Aspartoacyclase 17p Canavan disease 271900 Hydrolase Metabolic: glial None Argininosuccinate lyase 7q Argininosuccini- 207900 Lyase Metabolic (urea cycle): Cu ) Galactosyltransferase 7 progeroid form (glycosylation): ?CNS XH2, a ( ) syndrome; nonspeci XGPT1 ( XNP BBS1 BBS2 B4GALT7 B4GALT1 AVPR2 ATR ATRX ATP2A2 ASPM ASS ASPA ASL ATP7A Genesymbol Chr. OMIM function GO Drosophila FlyBase BLASTP 858 J. K. Inlow and L. L. Restifo ) h 40 59 81 45 54 11 163 146 136 124 Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ -value Ϫ Ϫ Ϫ Ϫ E continued ( g —— no. 0027844 0031148 0033226 0040336 f (*) 0003676 , ␥ (&) 0039993 (&) 0033578 Cct , others 0040069 (&) 0032195 (&) 0037709 , homolog(s) anhydrase 1 Carbonic CG1753 CG1882 vanin-like EG:BACR7C10.1 Tcp1-like CG17691 CG13232 CG4908 CG8199 e cation fi local toxicity systemic and systemic and cation Њ Њ Њ fi ciency systemic and local local energy fi Њ Њ neurotransmission,?myelination others development/ function; systemic and local toxicity toxicity hypothalamic- pituitary axis de modi (glycosylation): MR cause unknown local toxicity local toxicity (folding): MR cause unknown Biological function(s) d Molecular- APPENDIX (Continued) no. category c ciency 2 fi Clinical disorder de tubular acidosis function: CSF, sensorineural deafness ?systemic toxicity genital lipodystrophy function function: encephalopathy, andliver failure binding] phosphorylation): MR 2 disease type IAdisease type IB MR 2 MR 2 b ␣ ␤ -synthase 21q Homocystinuria 236200 Lyase Metabolic: CNS ␤ homolog-like 2q Tubulopathy, 603647 [Nucleotide Metabolic (oxidative cation 58 storage disease ?MR 2 fi Gene name arm BCS1 identi dehydrogenase E1 dehydrogenase E1 Cystathionine Comparative gene 3p Ichthyotic neutral lipid 604780 Hydrolase Metabolic (fatty acid): Carbonic anhydrase II 8q Osteopetrosis with renal 259730 Lyase CNS development/ Biotinidase 3p Multiple carboxylase 253260 Ligase Metabolic (various): MR Barttin 1p Bartter syndrome with 606412 Transporter MR cause unknown: None Seipin 11q Berardinelli-Seip con- 606158 Unknown ?CNS development/ Bardet-Biedl syndrome 6 20p Bardet-Biedl syndrome 6 604896 Chaperone Protein modi Branched-chain keto acid 6p MapleYeast syrup urine 248611 Oxidoreductase Metabolic (amino acid): Bardet-Biedl syndrome 4 15q Bardet-Biedl syndrome 4 600374 [Transferase] ?Protein Branched-chain keto acid 19q Maple syrup urine 248600 Oxidoreductase Metabolic (amino acid): ) a MKKS ( CBS CGI58 CA2 BTD BSND BSCL2 BBS6 BCKDHB BCS1L BBS4 BCKDHA Genesymbol Chr. OMIM function GO Drosophila FlyBase BLASTP Molecular Genetics of Mental Retardation 859 ) h 14 80 74 69 300 300 108 Ϫ Ϫ Ϫ Ϫ -value Ϫ Ϫ Ϫ E continued ( g —— —— —— —— —— no. 0003189 0032222 0036756 f , 0040066 ) 0015624 (&) 0051116 ¶ (& (&) 0030057 homolog(s) will die slowly nejire rudimentary CG5037 Ppt1 CG31116 CG5582 e Њ local Њ Њ systemic toxicity Њ ciency ammation local energy local toxicity local toxicity local toxicity local toxicity fi fl Њ Њ Њ Њ Њ development/func- tion; ?chromosome structure de (neuron) (neuron); ?synaptic function in CNS development/ function (myelin) Biological function(s) d Molecular- APPENDIX (Continued) no. category c ciency MR 2 fi Clinical disorder encephalopathy 2 infantileinfantile (neuron) (neuron) infantile local toxicity (neuron) infantile toxicity (neuron) cutaneous andarticular syndrome regulator (unknown): immune response; ?MR 2 type I factor scription-coupled): others] b oxidase 17p Progressive 602125 Transferase Metabolic (oxidative c Gene name arm subunit 10synthetase 1 mitochondrial to CPS1 de phosphorylation): MR neuronal 5neuronal 6neuronal 8 lipofuscinosis, late lipofuscinosis, late with MR function function 2 2 function 2 kidney, Bneuronal 2 type III lipofuscinosis, late ?systemic (peptide): toxicity MR 2 neuronal 3 function 2 CREB-binding protein 16p Rubinstein-Taybi 600140 Transcription Transcription Carbamoylphosphate 2q Hyperammonemia due 237300 Ligase Metabolic (urea cycle): Cytochrome Ceroid lipofuscinosis, 13qCeroid lipofuscinosis, Neuronal ceroid 15qCeroid lipofuscinosis, Neuronal ceroid 256731 8p Unknown Progressive epilepsy 606725 Unknown Lysosomal pathway: MR 600143 None Unknown ?Lysosomal pathway: MR None ?Lysosomal pathway: MR None Palmitoyl-protein 1p Neuronal ceroid 600722 Hydrolase Lysosomal pathway Chloride channel, 1pCeroid lipofuscinosis, Bartter syndrome 11p Neuronal ceroid 602023 Transporter MR cause 204500 unknown: Hydrolase Lysosomal pathway None Cryopyrin 1q Chronic neurologic 606416 Apoptosis ?Signaling pathway None Ceroid lipofuscinosis, 16p Batten disease 607042 Unknown Lysosomal pathway: MR ) Cockayne syndrome type I 5q Cockayne syndrome 216400 Transcription DNA repair (tran- [ ) thioesterase 1 ipofuscinosis, (lipoprotein): MR 2 CSA ) syndrome regulator regulation: CNS a ( CBP PPT1 ( ( CREBBP CPS1 COX10 CLN5 CLN6 CLN8 CLN1 CKN1 CLCNKB CLN2 CIAS1 CLN3 Genesymbol Chr. OMIM function GO Drosophila FlyBase BLASTP 860 J. K. Inlow and L. L. Restifo ) h 92 47 42 300 119 300 174 115 Ϫ Ϫ Ϫ -value Ϫ Ϫ Ϫ Ϫ Ϫ E continued ( g —— —— no. 0023081 0023184 0036211 f ) 0024242 ) 0032999 ¶ ¶ (& (& ) (&) 0036762 (&) 0030612 , others 0033524 ¶ ( homolog(s) 60B genghis khan, dystrophin Nucleolar protein at CG5946 CG7430 CG17528 Cyp49a1 CG5599 Њ e local energy systemic and Њ Њ ciency fi function (neurons, glia, blood vessel) de genes may contribute to phenotype function ?chromosome structure (Hh): CNS development/ function and differentiation local toxicity migration/ differentiation (?microtubule) toxicity Biological function(s) d Molecular- APPENDIX (Continued) no. category c Clinical disorder muscular dystrophies molecule CNS development/ Hoyeraal-Hreidarsson syndrome function; CNS development/ subcortical laminarheterotopia (microtubule): neuronal migration b Gene name arm protein kinase dystrophy 1 function; neighboring others] dehydrogenase disease type III MR 2 cytochrome b5reductase) type II development and reductase syndrome types I, II signaling pathway transacylase branched-chain disease type II MR 2 open reading frame 5 syndrome type I binding] function: neuronal (sterol 27-hydroxylase) xanthomatosis systemic and local Dystrophia myotonica 19q Congenital myotonic 605377 Kinase ?CNS development/ [ Dystrophin Xp Duchenne, Becker 300377 Structural Cytoskeleton (actin): Dyskerin Xq Dyskeratosis congenita; 300126 RNA binding RNA processing (rRNA): Dihydrolipoamide 7q Maple syrup urine 246900 Oxidoreductase Metabolic (glycolysis): Diaphorase (NADH- 22q Methemoglobinemia 250800 Oxidoreductase Metabolic (lipid): CNS 7-Dehydrocholesterol 11q Smith-Lemli-Opitz 602858 Oxidoreductase Metabolic (cholesterol): None Doublecortin Xq Lissencephaly; 300121 Protein binding Cytoskeleton Cytochrome P450 27A1 2q Cerebrotendinous 606530 Oxidoreductase Metabolic (lipid): MR 2 Chromosome X Xp Oral-facial-digital 300170 [Protein CNS development/ None Dihydrolipoamide 1p Maple syrup urine 248610 Transferase Metabolic (amino acid): a DM1 DMD DKC1 DLD DIA1 DHCR7 DCX CYP27A1 CXORF5 DBT Genesymbol Chr. OMIM function GO Drosophila FlyBase BLASTP Molecular Genetics of Mental Retardation 861 ) h 25 44 97 300 300 106 300 141 300 Ϫ Ϫ Ϫ -value Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ E continued ( g —— —— no. 0015844 0001179 0000576 0016718 0023023 0032477 ) E5 f , (&) 0032799 (&) (&) 0037327 (&) 0031464 (&) homolog(s) pigmentosum D expressed gene 3 mediator protein materials and methods Xeroderma haywire empty spiracles Rhythmically collapsin response CG5287 CG10166 EIF2-like CG3131 e cation cation fi fi neurotoxicity neurotoxicity Њ Њ development/ function (neuron) glia) development/ function function development/ function development/ function (thyroid): CNS development/ function Biological function(s) d Molecular- factor regulation: CNS APPENDIX (Continued) no. category c ciency ?MR 2 fi ciency, 602900 Transferase Chromosome structure: None fi ciency fi Clinical disorder syndrome function (neuron, syndrome de syndrome development/ glycosylation type Ijdue to DPYS de (glycosylation): CNS epilepsy syndrome (neuron) b ␣ Gene name arm empty spiracles 3B centromeric instability MR cause unknown kinase 3 mannosyltransferase 1dehydrogenase glycosylation type Ie due to DPYD (glycosylation): CNS ?MR 2 Xeroderma pigmentosum 19q Trichothiodystrophy; 126340 Protein binding Transcription (basal): Xeroderma pigmentosum 2q XPB/Cockayne 133510 Helicase Transcription/DNA Homolog 2 of Drosophila 10q Schizencephaly 600035 Transcription Transcription Dihydropyrimidine 1p Dihydropyrimidinuria 274270 Oxidoreductase Metabolic (pyrimidine): GlcNAc 1-P transferase 11q Congenital disorderDolichyl-phosphate of 191350 Transferase 20q Congenital disorder of Protein modi 603503 Transferase Protein modi DNA methyltransferase 20q Immunode Atrophin-1 12p Progressive myoclonus 125370 Protein binding Transcription regulation None (see Eukaryotic translation 2p Wolcott-Rallison 604032 Kinase Translation: CNS Dual oxidase 2 15q Congenital 606759 Oxidoreductase Hormone synthesis: ) Dihydropyrimidinase 8q Dihydropyrimidinuria 222748 Hydrolase Metabolic (pyrimidine): ) hypothyroidism endocrine function ) type D XPD/Cockayne CNS development/ ) type B syndrome repair: CNS ) initiation factor 2 DHP a ( XPD XPB PEK THOX2 ( ( ( ( ERCC2 ERCC3 EMX2 DPYD DPYS DPM1 DPAGT1 DNMT3B DRPLA EIF2AK3 DUOX2 Genesymbol Chr. OMIM function GO Drosophila FlyBase BLASTP 862 J. K. Inlow and L. L. Restifo ) h 23 50 64 79 130 123 177 Ϫ Ϫ Ϫ Ϫ -value Ϫ Ϫ Ϫ E continued ( g —— —— —— no. 0005592 0010389 0002887 f , 0022787 (&) 0010609 heart- breath- , ) ) , others 0037287 , ¶ ¶ (&) 0000488 (&) ( ( homolog(s) less less 201 Helicase 89B breathless CG2008 heartless mutagen-sensitive l(2)44DEa dumpy e cation None fi brils): MR fi kinase): CNS development/ function kinase): ?CNS development/ function development (neuron migration, glia) coupled): CNS development/ function development/ function (neuron) CNS development/ function Biological function(s) d Molecular- APPENDIX (Continued) no. category c c MR; 305400 Receptor Signaling pathway fi Clinical disorder Aarskog-Scottsyndrome signaling protein (phosphoinositide, Rho-type G protein) syndrome cause unknown muscular dystrophy (glycosylation): CNS craniosynostosis molecule (micro skeletal syndrome transcription: b Gene name arm receptor 2 synostosis syndromes (receptor tyrosine receptor 1 syndrome; others (receptor tyrosine long-chain 4 complementationgroup Acomplementationgroup C complementation complementation group A binding] group C binding] development/ development/ function function Fibroblast growth factor 10q Apert and other cranio- 176943 Receptor Signaling pathway Faciogenital dysplasia 1 XpFibroblast growth factor Nonspeci 8p Craniosynostosis; Apert 136350 Receptor Signaling pathway Fukutin 9q Fukuyama congenital 253800 [Transferase] Protein modi Xeroderma pigmentosum 13q XPG/Cockayne 133530 Hydrolase?, DNA repair Excision repair cross- 10q Cockayne syndrome type 133540 HydrolaseFanconi anemia DNA repair (transcrip-Fanconi anemia [ 16qFibrillin Fanconi 1 anemia 9q Fanconi anemia 227650 [Protein 15q 227645 Shprintzen-Goldberg [Protein DNA repair: ?CNS 134797 Structural DNA repair: None ?CNS Extracellular matrix None Fatty acid CoA ligase, Xq MRX63, MRX68 300157 Ligase Lipid synthesis: CNS ) type G syndrome other? (transcription- ) complementing 6 II; cerebrooculofacio- tion coupled), others] a XPG CSB ( ( FGFR2 FGD1 FGFR1 FCMD ERCC5 ERCC6 FANCA FANCC FBN1 FACL4 Genesymbol Chr. OMIM function GO Drosophila FlyBase BLASTP Molecular Genetics of Mental Retardation 863 ) h 65 32 19 95 33 300 127 300 127 Ϫ Ϫ Ϫ Ϫ Ϫ -value Ϫ Ϫ Ϫ Ϫ E continued ( g no. 0034567 0027607 0010389 f ) 0037735 ¶ ) 0014141 (*) 0041111 (& ¶ breath- ) 0028734 ) , others 0029889 , ¶ ¶ (& ( ( , others] 0004598 homolog(s) less fur2 CG16899 lilliputian dfmr1 CG15651 BcDNA:GH02536 cheerio CG4094 heartless e cation cation fi fi function development/ function development/ function (?neuronal differentiation) differentiation) function (neuronal migration) function cause unknown development/ function (?neuronal migration) kinase): ?CNS development/ function Biological function(s) d Molecular- function CNS development/ APPENDIX (Continued) no. category c c MR 309548 [Transcription Transcription fi ciency cycle): CNS fi Clinical disorder dyspraxia regulator regulation: CNS syndrome function (?neuronal heterotopia; others CNS development/ MR and cerebellarcysts function (glycosylation): CNS development/ Clausen disease function (proteoglycan): MR FH de b Gene name arm retardation 2 regulator] regulation: CNS retardation 1 retardation CNS development/ receptor 3 chondrodysplasias (receptor tyrosine Fraser syndrome gene 1 4q Fraser syndrome 607830 Unknown ?Extracellular matrix: [ Forkhead box P2 7q Developmental verbal 605317 Transcription Transcription Fragile site mental Xq X-linked nonspeci Fragile X mental Xq Fragile X mental 309550 RNA binding Translation regulation: Dymeclin 18q Dyggve-Melchior- 223800 Unknown ?Protein modi Filamin A Xq Periventricular nodular 300017 Protein binding Cytoskeleton (actin): Fukutin-related protein 19q Muscular dystrophy with 606596 Unknown ?Protein modi Fumarate hydratase 1q Fumaricaciduria due to 136850 Lyase Metabolic (citric acid Fibroblast growth factor 4p Craniosynostoses, 134934 Receptor Signaling pathway ••• a FRAS1 FOXP2 FMR2 FMR1 FLJ90130 FLNA FKRP FH FGFR3 Genesymbol Chr. OMIM function GO Drosophila FlyBase BLASTP 864 J. K. Inlow and L. L. Restifo ) h 76 75 163 129 124 300 118 138 Ϫ Ϫ -value Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ E continued ( g —— —— no. 0036169 0037567 0004057 0031845 0003162 0030289 f (&) 0035147 (&) 0031824 homolog(s) CG6128 CG9620 Zwischenferment CG12030 CG9232 CG9547 Punch CG1597 Њ Њ e Њ Њ synthe- 4 cation cation fi fi systemic toxicity (&) Њ ciency ciency fi fi CNS development/ function; ?neurotoxicity (glycoprotein): MR 2 local toxicity (neuron, glia) development/ function development/ function local toxicity function; MR 2 systemic energy de function; MR 2 systemic energy de sion (amines); systemic toxicity development/ function Biological function(s) d Molecular- APPENDIX (Continued) no. category c ciency 606999 Transferase Metabolic ciency 606953 Isomerase Metabolic fi fi ciency CNS development/ fi Clinical disorder kernicterus glycosylation type IIcgalactosemia (glycosylation): CNS (carbohydrate): ?CNS phenylalaninemia sis): neurotransmis- glycosylation type IIb (glycosylation): CNS b Gene name arm -Fucosidase 1 1p Fucosidosis 230000 Hydrolase Lysosomal pathway dehydrogenase dehydrogenaseuridylyltransferase hemolytic anemia;methyltransferase galactosemia de MR 2 (carbohydrate): MR 2 l - -Arginine:glycine 15q Inborn error of creatine 602360 Transferase Metabolic (creatine): None ␣ GTP cyclohydrolase 1 14q Atypical hyper- 600225 Hydrolase Metabolic (BH GDP-fucose transporter 1 11p Congenital disorder ofGlucose-6-phosphate 605881 Transporter Xq Protein Nonspherocytic modi Galactose-1-phosphate 305900 9p Oxidoreductase Metabolic (glycolysis): Transferase-de Galactose epimerase 1p Epimerase-de Guanidinoacetate 19pl Reversible brain creatine 601240 TransferaseGlutaryl-CoA Metabolic (creatine): None 19p Glutaricacidemia I 231670 Oxidoreductase Metabolic (amino acid): Glucosidase I 2p Congenital disorder of 601336 Hydrolase Protein modi ) amidinotransferase metabolism CNS development/ ••• a AGAT ( FUCA1 GCH1 FUCT1 G6PD GALT GALE GAMT GATM GCDH Genesymbol Chr. OMIM function GO Drosophila FlyBase BLASTP GCS1 Molecular Genetics of Mental Retardation 865 ) h 74 93 40 26 110 163 139 300 155 156 Ϫ Ϫ Ϫ Ϫ -value Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ E continued ( g —— no. 0001123 0037977 0037801 0004859 0004868 0027945 ] 0002525 ) f ¶ , 0025592 60A ␣ (& (&) 0033836 CG9092 Lamin C (&) 0040212 , , ) ) ¶ ¶ homolog(s) inhibitor Lamin G protein s CG18278 Dhap-at CG3999 cubitus interruptus CG3132 Glycerol kinase GDP dissociation pumpless e Њ local/ others local Њ Њ cAMP): (& → lament): glial local toxicity neuro/glial neuro/glial fi Њ Њ Њ ciency fi CNS function (?neuronal plasticity) toxicity (neuron, glia) ronal differentiation) local toxicity (neuron) MR 2 toxicity (neurotransmission) systemic energy de development/ function (astrocyte) ment/function (neurotransmission) MR 2 toxicity (neuro- transmission) Biological function(s) d Molecular- APPENDIX (Continued) no. category c llipo (glycosaminoglycan): ciency genesis): ?MR 2 fi fi Clinical disorder syndrome D) MR 2 punctata type II (glia: myelin) syndactyly ment/function (neu- types I, II (glycolipid): MR 2 to GK de b ) ing protein G): neuronal develop- ␣ Gene name arm brillary acidic 17q Alexander disease 137780 Structural Cytoskeleton (interme- [ fi -acyltransferase chondrodysplasia velopment/function -subunit osteodystrophy binding (GPCR sulfatase IIID (San O ␣ GM2-activator AB variant regulator colipid): MR 2 member 3 Greig cephalopoly- factor tion: CNS develop- (& protein molecule diate H protein inhibitor 1 (Rab GDI -Acetylglucosamine-6- 12q Mucopolysaccharidosis 607664 Hydrolase Lysosomal pathway -Galactosidase 1 3p GM1-gangliosidosis 230500 Hydrolase Lysosomal pathway N Glyceronephosphate 1q Rhizomelic 602744 Transferase Lipid synthesis: CNS de- Stimulatory G protein, 20q Albright hereditary 139320 Nucleotide Signaling pathway Ganglioside 5q Tay-Sachs disease, 272750 Enzyme Lysosomal pathway (gly- None Glycine decarboxylase 9p Glycine encephalopathy 238300 Oxidoreductase Metabolic (amino acid): GLI-Kruppel family 7p Acrocallosal syndrome; 165240 Transcription Transcription regula- ␤ Glycerol kinase Xp Hyperglycerolemia due 307030 Kinase Metabolic (gluconeo- Glial Guanine dissociation Xq MRX41, MRX48 300104 Receptor signal- Signaling pathway (small Glycine cleavage system 16q Glycine encephalopathy 238330 Transferase Metabolic (amino acid): ) a G6S ( GNS GNPAT GNAS GM2A GLDC GLI3 GLB1 GK GFAP GDI1 GCSH Genesymbol Chr. OMIM function GO Drosophila FlyBase BLASTP 866 J. K. Inlow and L. L. Restifo ) h 99 62 64 67 14 92 59 23 140 146 300 Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ -value Ϫ Ϫ Ϫ E continued ( g no. 0036992 0031877 0037332 0034417 0003074 0011577 f ) ) ¶ ) 0000316 ¶ ( ¶ ( (&) 0052495 (& , others] 0025334 , others 0041629 , others 0041629 homolog(s) CG2135 isomerase abnormally delayed PHDP CG11796 CG10399 Hexo2 Hexo2 CG14670 CG15117, CG32495 Phosphoglucose division cinnamon e , Њ Њ PC Њ ) systemic local toxicity , RTK, Wnt): Њ Њ ␤ MOCS1,2 ) systemic and local Њ toxicity function (myelin) PCC (glycolipid): MR 2 local toxicity (neuron) local toxicity (neuron) crine (pituitary) devel- opment/function local/systemic toxicity differentiation, ?plasticity) neurotransmission and metabolic (see function ?CNS development/ Biological function(s) d Molecular- APPENDIX (Continued) no. category c ciency integrity): ?MR 2 ciency tion (neuron survival, fi fi ciency toxicity (see also ciency type C function: fi fi Clinical disorder de (GM2-gangliosidosis) (glycolipid): MR 2 GSS de type VII (Sly (glycosaminoglycan): syndrome) MR 2 de syndrome type I transducer (TGF b Gene name arm methylglutaryl-CoAlyasepyruvate dioxygenase methylglutaric aciduria temic neurotoxicity; ?MR glial 2 development/ synthetase ple carboxylase 2 expressed in ES cells factor tion: CNS and endo- merase (neuroleukin) GPI de -Glucuronidase 7q Mucopolysaccharidosis 253220 Hydrolase Lysosomal pathway 4-Hydroxyphenyl- 12q Tyrosinemia type III 276710 Oxidoreductase Metabolic (amino acid): 3-Hydroxy-3- 1p 3-Hydroxy-3- 246450 Lyase Metabolic (various): sys- Hexosaminidase BHolocarboxylase 5q Sandhoff disease 21q Biotin-responsive multi- 606873 253270 Hydrolase Ligase Lysosomal pathway Metabolic (various): MR Hexosaminidase A 15q Tay-Sachs disease 606869 Hydrolase Lysosomal pathway ␤ Homeobox gene 3p Septooptic dysplasia 601802 Transcription Transcription regula- [ Glutathione synthetase 20q 5-Oxoprolinuria due to 601002 Ligase Metabolic (general cell Glucose-6-phosphate iso- 19q Hemolytic anemia due to 172400 Isomerase CNS development/func- Gephyrin 14q Molybdenum cofactor 603930 Protein binding CNS development/ Glypican 3 Xq Simpson-Golabi-Behmel 300037 Signal Signaling pathways a ••• HPD HMGCL HEXB HLCS HEXA GUSB HESX1 GSS GPI GPH GPC3 Genesymbol Chr. OMIM function GO Drosophila FlyBase BLASTP Molecular Genetics of Mental Retardation 867 ) h 76 86 83 13 64 136 168 118 Ϫ Ϫ Ϫ Ϫ Ϫ -value Ϫ Ϫ Ϫ E continued ( g —— —— —— no. 0035445 0004456 0032343 ) 0002968 f ¶ ) ¶ ) 0004197 (& ¶ (& (*)(*) 0039061 0039061 (& , others] 0026760 homolog(s) wings Tehao neuroglian Ir, Irk2 Ir, Irk2 CG12014 Serrate multiple edematous CG6201 e systemic fuel local toxicity local toxicity Њ Њ Њ ciency fi (neuron migration, differentiation, ?survival) de (Notch): CNS devel- opment/function (neuron, glia, ?blood vessel) (DA); ? CNS devel (neuron) ment/function ment/function (?cell survival) tegrin): ?CNS develop- ment/function ment/function (neuron, glia) Biological function(s) d Molecular- APPENDIX (Continued) no. category c Clinical disorder SPG1 molecule velopment/function hypercalciuric form type II (Huntersyndrome) (glycosaminoglycan): MR 2 type I (Hurlersyndrome) (glycosaminoglycan): MR 2 b -7 12q Congenital myopathy 600536 Receptor Signaling pathway (in- ␣ Gene name arm -Iduronidase 4p Mucopolysaccharidosis 252800 Hydrolase Lysosomal pathway -subunit type II transducer tiple): ?CNS develop- l ribosyltransferase ?neurotransmission accessoryprotein-like 1 transducer kine): ?CNS develop- factor 1 deafness and MR (RTK): CNS develop- ␥ - ␣ L1 cell adhesion molecule Xq MASA syndrome; HSAS; 308840 Cell adhesion Cell adhesion: CNS de- Potassium channel J11, 11p Hyperinsulinemic hypo- 600937 Transporter Endocrine (pancreas): Potassium channel J1, 11q Bartter syndrome type II, 600359 Transporter MR cause unknown: Iduronate 2-sulfatase Xq Mucopolysaccharidosis 309900 Hydrolase Lysosomal pathway Hypoxanthine phospho- Xq Lesch-Nyhan syndrome 308000 Transferase Metabolic (purine): None Jagged 1 20p Alagille syndrome 601920 Ligand Signaling pathway Interleukin 1 receptor Xp MRX34 300206 Signal Signaling pathway (cyto- [ Integrin Insulin-like growthInhibitor 12q of KB kinase, Growth retardation with 147440 Xq Ligand Incontinentia pigmenti 300248 Signal Signaling pathway Signaling None pathway (mul- None ) inwardly rectifying antenatal ?systemic toxicity ) ) inwardly rectifying glycemia of infancy MR 2 a ROMK Kir6.2 NEMO ( ( ( L1CAM KCNJ11 KCNJ1 IDS HPRT IDUA JAG1 IL1RAPL1 ITGA7 IGF1 IKBKG Genesymbol Chr. OMIM function GO Drosophila FlyBase BLASTP 868 J. K. Inlow and L. L. Restifo h ) 72 79 19 300 162 300 300 300 Ϫ Ϫ Ϫ -value Ϫ Ϫ Ϫ Ϫ Ϫ E continued ( g —— —— no. 0037215 0005278 0032679 ) 0015754 ) 0041706 * ¶ , 0027611 f ) 0004002 (& ¶ (& (&) 0039877 (&) , others ( homolog(s) others factor CG12582 M(2)21AB CG2118 BcDNA:GH02419 bicoid stability Lissencephaly-1 CG3253 wing blister e Њ Њ cation fi local and Њ ciency local energy fi Њ systemic neuroglial toxicity coprotein): MR 2 local toxicity (neuron, glia) development/ function: neurotrans- mission (DA, 5HT) coprotein): MR 2 local toxicity (neuron, glia) vessel de (neuron migration, ?proliferation) 2 development/ function toxicity (neuron, glia) migration; myelin) Biological function(s) d ed en- Cytoskeleton (micro- fi Molecular- APPENDIX (Continued) no. category c ciency function (glia: myelin) cient muscular molecule CNS development/ fi fi Clinical disorder de subcortical laminar zyme tubule): CNS develop- de dystrophy function (neuronal -Mannosidosis 248510 Hydrolase Lysosomal pathway (gly- -Mannosidosis 248500 Hydrolase Lysosomal pathway (gly- ␤ ␣ b ␣ -2 (merosin) 6q Congenital merosin- 156225 Structural Extracellular matrix: ␣ Gene name arm transferase transferase I/III CNS development/ lysosomal containing protein Canadian type phosphorylation): MR ferase-like protein dystrophy ID (glycosylation): CNS acetylhydrolase 1B membrane protein 2 IIB cause unknown; ?local -Mannosidase 4q -Mannosidase 2B1, 19q Monoamine oxidase A Xp BrunnerMethionine syndrome adenosyl- 10q 309850 Methionine Oxidoreductase adenosyl- Metabolic (amine): CNS 250850 None Transferase Metabolic (methionine): 3-Methylcrotonyl-CoA 3q 3-Methylcrotonyl- 210200 Ligase Metabolic (amino acid): ␤ ␣ Leucine-rich PPR motif- 2p Leigh syndrome, French- 607544 [DNA binding] Metabolic (oxidative Platelet-activating factor 17p Lissencephaly; 601545 Unclassi Acetylglucosaminyltrans- 22q Congenital muscular 603590 Transferase Protein modi Lysosome-associated Xq Glycogen storage disease 309060 Protein binding Lysosomal pathway: MR None Laminin ) carboxylase 1 glycinuria I MR 2 a ) heterotopia ment/function MCCA PAFAH- ( 1B1 ( MAOA MAT1A MCCC1 MANBA MAN2B1 LRPPRC LIS1 LARGE LAMP2 LAMA2 Genesymbol Chr. OMIM function GO Drosophila FlyBase BLASTP Molecular Genetics of Mental Retardation 869 ) h 32 30 12 57 29 45 13, 100 300 123, Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ -value Ϫ Ϫ Ϫ E continued ( g —— —— no. 0036904 0039738 0031662 f ) 0051721 i ¶ ( ] 0033664 (&) 0042083 homolog(s) CG10238 Mocs1 CG8981 CG8743 CG31721 Mgat2 CG3267 CG3792 e Њ Њ local Њ cation cation fi fi local and Њ local toxicity (neuron, glia) ?CNS development/ function tubule): CNS develop- ment/function (?pro- liferation) systemic neuroglial toxicity toxicity (neuron) development/ function colipid): MR 2 velopment/function: neurogenesis local toxicity (neuron, glia) development/ function Biological function(s) d ed Metabolic (amino acids orfs A and B: 0039280 ed Metabolic (amino acids orfs A and B: 0036122 fi fi Molecular- APPENDIX (Continued) no. category c ciency 606761 Lyase Metabolic (?fatty acid): none fi ciency type B enzyme and others): MR 2 ciency type A enzyme and others): MR 2 fi fi Clinical disorder encephalopathy;other ment/function: neu- ron differentiation b -Acetylglucos- 14q Congenital disorder of 602616 Transferase Protein modi Gene name arm N decarboxylase protein 2aminyltransferase II MRX16; glycosylation neonatal type IIa (glycosylation): CNS tion; CNS develop- -1,2- Molybdopterin synthase, 5q Molybdenum cofactor 603708 Unclassi Malonyl-CoAMolybdenum 16q MLYCD de 6p Molybdenum cofactor 603707 Unclassi Mucolipin 1Microcephalin 19p Mucolipidosis IV 8p Primary microcephaly 1 607117 605248 [DNA Transporter binding] (?DNA repair):Midline CNS 1 de- Lysosomal pathway (gly- [ Xp Opitz syndrome type I 300000 Protein binding Cytoskeleton (micro- Methyl-CpG-binding Xq Rett syndrome; 300005 DNA binding Transcription regula- None ␤ 3-Methylcrotonyl-CoA 5q 3-Methylcrotonyl- 210210 Ligase Metabolic (amino acid): Mannose-P-dolichol 17p Congenital disorder of 604041 [Chaperone] Protein modi ) small and large subunits de ) carboxylase 2 glycinuria II MR 2 orfs ) utilization defect 1 glycosylation type If (glycosylation): CNS ( a ) cofactor synthesis 1 de orfs A, B MCCB Lec35 ( A, B ( ( MOCS2 MOCS1 MLYCD MCOLN1 MCPH1 MID1 MECP2 MGAT2 MCCC2 Genesymbol Chr. OMIM function GO Drosophila FlyBase BLASTP MPDU1 870 J. K. Inlow and L. L. Restifo ) h 16 46 65 21 79 52 107 300 Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ -value Ϫ Ϫ E continued ( g —— no. 0013697 50% id 0013692 51% id 0013684 0036157 0013678 0013676 0013674 0013675 0013672 f , others] 0015623 homolog(s) Cpr mt:tRNA:K mt:tRNA:E mt:ND5 CG7560 mt:Cyt-b mt:CoIII mt:CoI mt:CoII mt:ATPase6 e ciency ciency ciency ciency ciency ciency ciency ciency local energy local energy local energy local energy local energy local energy local energy local energy fi fi fi fi fi fi fi fi Њ Њ Њ Њ Њ Њ Њ Њ de de function (myelin) function (myelin) 2 de 2 function (myelin) de de 2 de 2 de de Biological function(s) d Molecular- APPENDIX (Continued) no. category - 156570 Transferase Metabolic (methionine): None fi c ciency CNS development/ fi Clinical disorder lap syndrome; others 2 ciency, cblG type CNS development/ MELAS 2 neuropathy, ataxia,retinitis pigmentosa phosphorylation): MR 2 encephalopathy 2 b oxidase Mt Leigh-like 516050 Oxidoreductase Metabolic (oxidative oxidase Mtoxidase Mitochondrial Mt Mitochondrial 516030 Oxidoreductase Metabolic (oxidative 516040 Oxidoreductase Metabolic (oxidative c c c Gene name arm transfer RNA MERRF/MELAS over- drial translation): MR reductaseacid transfer RNA megaloblastic with anemia diabetes mellitus CNS development/ drial translation): MR reductase subunit 5 syndrome phosphorylation): MR folate reductase MTHFR de subunit IIIIII encephalopathy; drial disorder phosphorylation): MR phosphorylation): MR subunit II encephalopathy phosphorylation): MR subunit I syndromic phosphorylation): MR Mitochondrial lysine Mt MERRF syndrome; 590060 Transfer RNA Metabolic (mitochon- Methionine synthaseMitochondrial glutamic 5p Homocystinuria- Mt Encephalomyopathy 602568 590025 Transferase Transfer RNA Metabolic (mitochon- Metabolic (methionine): [ Methionine synthase 1q Methylcobalamin de NADH-ubiquinone oxido- Mt Leigh syndrome, MELAS 516005 Oxidoreductase Metabolic (oxidative Methylenetetrahydro- 1p Homocystinuria due to 607093 Oxidoreductase Metabolic (methionine): Cytochrome b of complex Mt Multisystem mitochon- 516020 Oxidoreductase Metabolic (oxidative Cytochrome Cytochrome Cytochrome ATP synthase subunit 6 Mt Leigh syndrome; 516060 Transporter Metabolic (oxidative a MTTK MTRR MTTE MTR MTND5 MTHFR MTCYB MTCO3 MTCO1 MTCO2 MTATP6 Genesymbol Chr. OMIM function GO Drosophila FlyBase BLASTP Molecular Genetics of Mental Retardation 871 ) h 66 36 33 300 300 145 300 Ϫ Ϫ Ϫ -value Ϫ Ϫ Ϫ Ϫ E continued ( g —— no. 0039669 0031021 0039909 0014417 0026198 0017566 0013708 48% id 0013706 47% id 0013699 56% id f ) 0015933 ¶ (& homolog(s) CG111913 CG2014, CG9172 CG12203 CG1970, ESTS:172F5T nbs ND75 didum mt:tRNA:V mt:tRNA:S:UCN mt:tRNA:L:UUR e local energy local energy local toxicity Њ Њ Њ ciency ciency ciency ciency ciency ciency ciency local energy local energy local energy local energy local energy fi fi fi fi fi fi fi Њ Њ Њ Њ Њ MR 2 de MR 2 de de 2 de MR 2 (?growth factor): ?neuronal survival 2 de de drial translation): MR 2 de 2 drial translation): MR 2 Biological function(s) d Molecular- APPENDIX (Continued) no. category c ciency phosphorylation): MR fi Clinical disorder (neuroectodermalmelanolysosomaldisease)syndrome opment/function: ?neurotransmission binding (pre/postsynaptic) opment/function b - 17q Mucopolysaccharidosis 252920 Hydrolase Lysosomal pathway d - ␣ Gene name arm reductase Fe-S p. 7 phosphorylation): reductase Fe-S p. 4 phosphorylation): reductase Fe-S p. 2 phosphorylation): MR glucosaminidase type IIIB (glycosaminoglycan): reductase Fe-S p. 1 de transfer RNA transfer RNA 1 syndrome drial translation): MR transfer RNA 1 -acetyl- NADH-ubiquinone oxido- 19p Leigh syndrome 601825 Oxidoreductase Metabolic (oxidative NADH-ubiquinone oxido- 5q Leigh syndrome 602694 Oxidoreductase Metabolic (oxidative NADH-ubiquinone oxido- 1q Encephalomyopathy 602985 Oxidoreductase Metabolic (oxidative Nibrin 8q Nijmegen breakage 602667 Protein (DNA?) DNA repair: CNS devel- NADH-ubiquinone oxido- 2q Mitochondrial complex I 157655 Oxidoreductase Metabolic (oxidative Myosin VA 15q Elejalde syndromeNorrin 160777 Motor protein Cytoskeleton: CNS devel- Xp Norrie disease 310600 Ligand ?Signaling pathway None Mitochondrial valine Mt Leigh syndrome 590105 Transfer RNA Metabolic (mitochon- Mitochondrial serine Mt MERRF/MELAS overlap 590080 Transfer RNA Metabolic (mitochon- Mitochondrial leucine Mt MELAS syndrome 590050 Transfer RNA Metabolic (mitochon- a NDUFS7 NDUFS4 NDUFS2 NBS1 NDUFS1 MYO5A NAGLU N NDP MTTV MTTS1 MTTL1 Genesymbol Chr. OMIM function GO Drosophila FlyBase BLASTP 872 J. K. Inlow and L. L. Restifo ) h 73 24 81 19 75 105 168 113 300 300 300 Ϫ Ϫ Ϫ Ϫ Ϫ -value Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ E continued ( g no. 0024320 0015269 0017567 ) 0023508 f ¶ (& ) 0039559 (&) 0035348 ¶ (&) 0036898 (&) 0031381 (*) 0035539 , others 0031771 NPC1b bromin 1 ) (& , fi ¶ , others] 0010407 homolog(s) Ror EG:86E4.5 CG8782 Mes-4 CG7291 NPC1 CG16758 Neuro CG7447 CG9140 ND23 e Њ local local Њ Њ ciency fi local Њ ciency ciency local toxicity local energy local energy fi fi Њ Њ Њ naling pathway (small/ ing: CNS develop- ment/function (myelin) energy de ment/function ment/function (neuron) toxicity (neuron, glia) toxicity (neuron, glia) 2 plasticity (glycolipid): MR 2 local toxicity de de phosphorylation): MR 2 Biological function(s) d Molecular- signaling heterotrimeric (& protein G proteins): ?synaptic APPENDIX (Continued) no. category c ciency 164050 Transferase Metabolic (purine): ?MR fi bromatosis type I 162200 Receptor Sig fi Clinical disorder b bromin 17q Neuro Gene name arm fi avoprotein 1 syndrome 2 syndrome of Lowe syndrome and/or protein sort- aminotransferase atrophy ?MR 2 SET domain protein 1 (cerebral gigantism) regulator tion: CNS develop- type C2 type C2 lesterol): MR 2 type C1 types C1, D lesterol): MR 2 phosphorylase oxidoreductasefl Alexander phosphorylation): MR oxidoreductase Fe-S p. 8 Oculocerebrorenal Xq Lowe oculocerebrorenal 309000 Phosphatase Signaling pathway (PI) Neurotrophic tyrosine 1q Congenital insensitivity 191315 Receptor Signaling pathway [ Ornithine ketoacid 10q Gyrate chorioretinal 258870 Transferase Metabolic (amino acid): Nuclear receptor binding 5q Sotos syndrome 606681 Transcription Transcription regula- Niemann-Pick disease 14q Niemann-Pick disease 601015 Transporter Lysosomal pathway (cho- Niemann-Pick disease 18q Niemann-Pick disease 607623 Transporter Lysosomal pathway (cho- Nucleoside 14q Purine NP de Neuro Neuraminidase 6p Sialidosis type II 256550 Hydrolase Lysosomal pathway NADH-ubiquinone 11q Leigh syndrome, 161015 Oxidoreductase Metabolic (oxidative NADH-ubiquinone 11q Leigh syndrome 602141 Oxidoreductase Metabolic (oxidative ) kinase receptor type 1 to pain with anhydrosis (RTK): CNS develop- a TRKA ( OCRL NTRK1 OAT NSD1 NPC2 NPC1 NP NF1 NEU1 NDUFV1 NDUFS8 Genesymbol Chr. OMIM function GO Drosophila FlyBase BLASTP Molecular Genetics of Mental Retardation 873 ) h 61 87 59 17 82 139 118 148 300 123 153 Ϫ Ϫ Ϫ Ϫ Ϫ -value Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ E continued ( g no. 0029721 0027580 f (&) 0000455 (&) ] 0003189 &) 0042083 &) 0039877 * * CG7024 ) 0030685 ( ( ) 0014001 , ¶ ¶ (& homolog(s) GH06348 rudimentary Dipeptidase C CG7010 BcDNA: CG3267 CG2118 Graf e local Њ ciency fi systemic toxicity systemic toxicity systemic toxicity systemic toxicity Њ Њ Њ Њ ciency local energy fi Њ (?extracellular matrix): MR cause unknown energy de ?CNS development/ function; MR 2 MR 2 G): ?cytoskeleton (actin); CNS develop- ment/function de opment/function (thyroid) MR 2 MR 2 (neuron, glia) neurotransmission (glutamate) (actin); CNS develop- ment/function Biological function(s) d Molecular- factor tion: endocrine devel- ing protein G): cytoskeleton APPENDIX (Continued) no. category c ciency MR 2 fi ciency 312170 Oxidoreductase Metabolic (glycolysis): fi ciency 170100 Hydrolase Protein degradation fi Clinical disorder disease 2 encephalopathy systemic toxicity; b Gene name arm ␣ -subunit -subunit E1- carboxylase, ␤ kinase 3 carboxylase, ␣ hydroxylase transcarbamylase to OTC de Peptidase D (prolidase) 19q PEPD de Pyruvate dehydrogenase, Xp PDHA1 de Pantothenate kinase 2 20p Hallervorden-Spatz 606157 Kinase Metabolic (various): MR fumble 0011205 Paired box gene 8Pyruvate carboxylase 2q Thyroid dysgenesis 11q Leigh necrotizing 167415 Transcription Transcription 266150 regula- Ligase shaven (&) Metabolic: local & 0005561 Propionyl-CoA 3q Propionicacidemia 232050 Ligase Metabolic (amino acid): Phenylalaninep21-activated protein 12q Xq Phenylketonuria MRX30, MRX47 261600 Oxidoreductase 300142 Metabolic Kinase (amino acid): Henna (&) Signaling pathway (small 0001208 Pak (& Propionyl-CoA 13q Propionicacidemia 232000 Ligase Metabolic (amino acid): Ornithine Xp Hyperammonemia due 311250 Transferase Metabolic (urea cycle): [ Oligophrenin 1 Xq MRX60 300127 Receptor signal- Signaling pathway (small a PEPD PDHA1 PANK2 PAX8 PC PCCB PAH PAK3 PCCA OTC OPHN1 Genesymbol Chr. OMIM function GO Drosophila FlyBase BLASTP 874 J. K. Inlow and L. L. Restifo ) h 32 29 23 26 71 82 31 51 85 102 Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ -value Ϫ E continued ( g no. 0037019 0033812 0031282 0035233 0023516 0035876 0036484 f (&) 0033564 (&) 0013563 (&) 0035922 homolog(s) CG3947 CG4663 CG3639 CG7864 CG6486 EG:63B12.5 CG7081 CG6859 CG11919 l(3)70Da e function (neuron migration, glia) function (neuron migration, glia) function (neuron migration, glia) function (neuron migration, glia) migration, glia) function (neuron migration, glia) function (neuron migration, glia) migration, glia) migration, glia) function (neuron migration, glia) Biological function(s) d Molecular- APPENDIX (Continued) no. category c Clinical disorder punctata type I function (neuron disease function (neuron disease; NALD function (neuron b Gene name arm biogenesis factor 16) binding] CNS development/ biogenesis factor 13) NALD CNS development/ biogenesis factor 12) CNS development/ biogenesis factor 10) NALD CNS development/ biogenesis factor 7) chondrodysplasia CNS development/ biogenesis factor 6) binding CNS development/ biogenesis factor 3) binding] CNS development/ biogenesis factor 1) infantile Refsum binding CNS development/ Peroxin 16 (peroxisome 11p Zellweger syndrome 603360 [Protein Metabolic (oxidation): Peroxin 13 (peroxisome 2p Zellweger syndrome; 601789 Protein binding Metabolic (oxidation): Peroxin 12 (peroxisome 17p Zellweger syndrome 601758 Protein binding Metabolic (oxidation): Peroxin 10 (peroxisome 1p Zellweger syndrome; 602859 Protein binding Metabolic (oxidation): Peroxin 7 (peroxisome 6q Rhizomelic 601757 Receptor Metabolic (oxidation): Peroxisome receptor 1 12p Zellweger syndrome; 600414 Receptor Metabolic (oxidation): Peroxin 3 (peroxisome 6q Zellweger syndrome 603164 [Protein Metabolic (oxidation): Peroxisomal membrane 8q Zellweger syndrome; 170993 Protein binding Metabolic (oxidation): Peroxin 6 (peroxisome 6p Zellweger syndrome 601498 Nucleotide Metabolic (oxidation): Peroxin 1 (peroxisome 7q Zellweger syndrome; 602136 Nucleotide Metabolic (oxidation): ) protein 3 infantile Refsum CNS development/ ) NALD CNS development/ a PXMP3 PXR1 ( ( PEX16 PEX13 PEX12 PEX10 PEX7 PEX5 PEX3 PEX2 PEX6 PEX1 Genesymbol Chr. OMIM function GO Drosophila FlyBase BLASTP Molecular Genetics of Mental Retardation 875 ) h 79 35 47 29 16 74 13 161 158 164 Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ -value Ϫ Ϫ Ϫ E continued ( g —— no. 0020018 0003995 0003075 0037092 0036300 ) 0038738 * f (&) 0003292 , (&) 0036030 ,others( ] 0034521 CG9961 homolog(s) , idase lacking Mgat1 protoporphyrinogenox- CG6767 ventral veins CG4572 rotated abdomen M6 CG10688 Pgk e CNS others (*) local → Њ cation [ cation cation fi fi fi MR cause unknown synthesis): MR cause unknown toxicity (neuron) development/ function (neuronal migration) tion (pituitary) development/ function (glycosylation): CNS development/ function (neuronal migration) plasticity) (myelin) development/ function function (neuron migration, glia) Biological function(s) d Molecular- APPENDIX (Continued) no. category c ciency factor endocrine dev/func- fi ciency function (?synaptic fi Clinical disorder rjeson-Forssman- 300414 Transcription ?Transcription: ?CNS de- None de diseaseglycosylation type Ia molecule tion: oligodendrocyte (glycosylation): CNS ¨ b -mannosyl- 9q Walker-Warburg 607423 Transferase Protein modi O Gene name arm nger 6 Lehmann syndrome regulator velopment/function phate synthetase 1 pyrimidine synthesis): oxidase protein (cathepsin A) colipid): MR 2 transferase 1 syndrome (glycosylation): CNS transferase I.2 kinase 1fi MR due to PGK1 ?CNS development/ biogenesis factor 19) binding] CNS development/ -Acetylglucosaminyl- 1p Muscle-eye-brain disease 606822 Transferase Protein modi -Galactosidase protective 20q Galactosialidosis 256540 Protein binding Lysosomal pathway (gly- Phosphoribosylpyrophos- Xq PRPS1-related gout 311850 Kinase Metabolic (purine, Protoporphyrinogen 1q Variegate porphyria 600923 Oxidoreductase Metabolic (heme POU domain class 1 3p␤ Combined pituitary 173110 Transcription Transcription: Protein Plant homeodomain-like Xq Bo Phosphomannomutase 2 16p Congenital disorder of 601785 Isomerase Protein modi Proteolipid protein 1 Xq Pelizaeus-Merzbacher 300401 Structural CNS development/func- Peroxin 19 (peroxisome 1q Zellweger syndrome 600279 [Protein Metabolic (oxidation): CG5325 0032407 Phosphoglycerate Xq Hemolytic anemia and 311800 Kinase Metabolic (glycolysis): ) transcription factor 1 hormone de a PIT1 ( PRPS1 PPOX POU1F1 PPGB POMT1 PHF6 PMM2 POMGNT1 N PLP1 PEX19 PGK1 Genesymbol Chr. OMIM function GO Drosophila FlyBase BLASTP 876 J. K. Inlow and L. L. Restifo ) h 72 27 71 40 70 114 127 300 300 Ϫ Ϫ Ϫ Ϫ Ϫ -value Ϫ Ϫ Ϫ Ϫ E continued ( g —— —— no. 0000416 0037146 0003141 0035964 f ) 0000382 ) 0023479 ¶ ¶ (& ) 0026379 (& (&) 0003892 (&) 0003892 ¶ (& homolog(s) reductase corkscrew Saposin-related patched patched Pten Tequila CG7470 purple Dihydropteridine e local Њ synthe- ): 4 4 systemic toxic- Њ migration/ differentiation) identity, proliferation) function (?neuron identity, proliferation) function (synapse) sion (amines); sys- temic toxicity ?plasticity) (amines); systemic toxicity ment/function: ?neu- ron differentiation MR 2 ity; ?neuromodulation Biological function(s) d Molecular- APPENDIX (Continued) no. category c ciency sis): neurotransmis- fi c MR CNS development/ ciency toxicity (glia: myelin) fi fi Clinical disorder syndrome; others function (neuron leukodystrophy,PSAP de regulator colipid): MR 2 basal cell nevussyndromecarcinoma syndrome CNS development/ CNS development/ function (?neuron syndrome; others tion (synaptogenesis, syndrome regulator] tion; CNS develop- b Gene name arm homolognonreceptor type 11 Bannayan-Zonana CNS development/ ment/function (neurotrypsin)patched nonspeci patched (nectin 1) ectodermal dysplasia molecule development/func- hydropterin synthase due to PTS de late synthetase dine reductase phenylketonuria neurotransmission -1-Pyrroline-5-carboxy- 10q Hyperammonemia 138250 Oxidoreductase Metabolic (amino acid): Protein-tyrosine6-Pyruvoyltetra- 12q Noonan syndrome 1; 11q 176876 Hyperphenylalaninemia Phosphatase 261640 Lyase Signaling pathway (vari- Metabolic (BH Homolog of Drosophila 9q Holoprosencephaly 7; 601309 Receptor Signaling pathway (Hh): Homolog 2 of Drosophila 1p Nevoid basalPhosphatase cell and tensin 10q Cowden syndrome; 603673 Receptor 601728 Phosphatase Signaling pathway (Hh): Signaling pathway (PI): Prosaposin 10q Metachromatic 176801 Enzyme Lysosomal pathway (gly- Serine protease 12 4q Autosomal recessive 606709 Hydrolase Protein degradation: Poliovirus receptor-like 1 11q Cleft lip/palate-␦ 600644 Cell adhesion Cell-cell adhesion: CNS None Retinoic acid induced 1 17p Smith-Magenis 607642 [Transcription ?Transcription regula- none Quinoid dihydropteri- 4p Atypical 261630 Oxidoreductase Metabolic (BH ) phosphatase, LEOPARD syndrome ous): ?CNS develop- a SHP2 ( PTPN11 PTS PTCH PTCH2 PTEN PSAP PRSS12 PVRL1 PYCS RAI1 Genesymbol Chr. OMIM function GO Drosophila FlyBase BLASTP QDPR Molecular Genetics of Mental Retardation 877 ) h 87 83 80 56 139 300 300 300 Ϫ Ϫ Ϫ Ϫ -value Ϫ Ϫ Ϫ Ϫ E continued ( g —— —— no. 0017539 0031656 0031899 f (&) ) 0004644 ¶ ) 0025360 (&) 0038660 ) 0011285 (& ¶ ¶ &) 0038947 CG5718 (& * (& , ( -driven anion ϩ homolog(s) exchanger 1 Na Optix hedgehog CG14291 sar1 S6kII Scs-fp CG8885 e local toxicity Њ ciency ciency local energy local energy fi fi Њ Њ fate, differentiation; morphogenesis) CNS development (neuron and glia iden- tity, differentiation) MR 2 de 2 development/ function tion, differentiation) de signaling pathway (Hh); ?CNS develop- ment/function 2 tion): ?CNS develop- ment/function (neuron, glia) Biological function(s) d Molecular- factor development (cell APPENDIX (Continued) no. category c n-Lowry syndrome; 300075 Kinase Signaling pathway Clinical disorder fi Marinesco-Sjogren syndrome lissencephalysyndrome ous): CNS develop- ment (neuron migra- encephalomyopathy phosphorylation): MR b 22q Fatal infantile cardio- 604272 Chaperone Metabolic (oxidative SCO2 3 Gene name arm sine oculis sulfohydrolase type IIIA (glycosaminoglycan): complex subunit A phosphorylation): MR dehydrogenase) cotransporter) -Sulfoglucosamine 17q Mucopolysaccharidosis 605270 Hydrolase Lysosomal pathway Solute carrier 4A4 4q Renal tubular acidosis II 603345 Transporter Transport (pH regula- Homolog 3 of Drosophila 2p Holoprosencephaly 2 603714 Transcription Transcription reg: CNS Sonic hedgehog 7q Holoprosencephaly 3 600725 Ligand Signaling pathway(Hh): N Sar1-ADP-ribosylation 5q Chylomicron retention 607690 Nucleotide Transport (lipids): MR Ribosomal S6 kinase 2 Xp Cof Succinate dehydrogenase 5p Leigh syndrome 600857 Oxidoreductase Metabolic (oxidative Reelin 7q Norman-Roberts 600514 Ligand Signaling pathway (vari- none Sterol C5-desaturase 11q Lathosterolosis 602286 Oxidoreductase Metabolic (cholesterol): None Homolog of yeast ) MRX19 (growth factor): ?CNS ) ) factor 2 disease with binding cause unknown ) (Na-HCO ) (lathosterol HSS a ( RPS6KA3 SAR1B SC5D NBC1 ( ( ( ( SLC4A4 SIX3 SHH SGSH SARA2 RSK2 SDHA RELN SC5DL SCO2 Genesymbol Chr. OMIM function GO Drosophila FlyBase BLASTP 878 J. K. Inlow and L. L. Restifo ) h 29 25 64 71 94 84 124 300 300 156 124 Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ -value Ϫ Ϫ Ϫ Ϫ Ϫ E continued ( g no. 0036272 ) 0039915 * f (&) 0025698 ) 0029123 ¶ (& (&) 0024288 (&) 0034997 (&) 0030218 , others 0038799 , others 0036279 , others 0039844 , others 0017448 ,others( homolog(s) Sox100B CG4300 SoxNeuro CG3376 CG4288 CG1628 CG4357 BEST:CK01510 CG1607 CG2187 CG1732 e Њ local local Њ Њ local toxic- ciency Њ fi systemic toxicity Њ oligodendrocyte differentiation) ment/function (neurogenesis) function (neuron excitability) toxicity (neuron) ?and CNS develop- ment/function MR 2 tion (myelin, neuron) energy de systemic toxicity roid): CNS develop- ment/function function; MR 2 Biological function(s) d Molecular- APPENDIX (Continued) no. category c ciency factor tion: CNS develop- fi ciency syndrome CNS development/ fi Clinical disorder syndrome, neurologicvariant factor regulation: CNS development (myelin: hormone de syndrome ?CNS development/ Salla disease ity (neuron, glia) hypercalciuric form ?systemic toxicity b L 14q Lysinuric protein 603593 Transporter Transport (dibasic ϩ Gene name arm transporter 1) (sialin) storage disorder; ous): MR 2 transporter 1) amino acid intolerance amino acids): ?MR 2 (Na-I symporter) hormonogenesis I docrine function (thy- SRY-related HMG-box 10 22q Waardenburg-Shah 602229 Transcription Transcription SRY-related HMG-box 3 Xq MR with growth 313430 Transcription Transcription regula- Spermine synthase Xp Snyder-Robinson 300105 Transferase Metabolic (polyamine): Sphingomyelin 11p Niemann-Pick disease, 257200 Hydrolase Lysosomal pathway (gly- Solute carrier 25A15 13q HHH syndrome 603861 Transporter Transport (ornithine): Solute carrier 17A5 6q Infantile sialic acid 604322 Transporter Lysosomal pathway (vari- Solute carrier 12A6 15q Agenesis of corpus 604878 Transporter Transport (ions): CNS Solute carrier 7A7 (y Solute carrier 12A1 (Na-K- 15q Bartter syndrome type I, 600839 Transporter Transport (ions): MR Solute carrier 6A8 Xq X-linked creatine 300036 Transporter Transport (creatine): Solute carrier 5A5 19p Genetic defect in thyroid 601843 Transporter Transport (iodide): en- ) (ornithine ) Cl transporter 2) antenatal cause unknown; ) (creatine transporter) de ) (K-Cl cotransporter) callosum (ACCPN) development/func- ) phosphodiesterase 1 type A colipid): MR 2 a ORNT1 ASM KCC3 NKCC2 CRTR ( ( ( ( ( SOX10 SOX3 SMS SMPD1 SLC25A15 SLC17A5 SLC12A6 SLC7A7 SLC12A1 SLC6A8 SLC5A5 Genesymbol Chr. OMIM function GO Drosophila FlyBase BLASTP Molecular Genetics of Mental Retardation 879 ) h 15 61 37 33 25 57 127 130 Ϫ Ϫ Ϫ Ϫ Ϫ Ϫ -value Ϫ Ϫ E continued ( g —— —— no. 0027359 0000024 0033748 0030966 0029117 ) 0000568 * f ) 0033055 ¶ (& (&) 0030558 , others] achintya , ,others( homolog(s) sterase Acetylcholine- Tim8 CG7861 E75B vismay CG1461 CG7280 Surfeit 1 e systemic local toxicity Њ Њ ciency ciency local energy local energy fi fi Њ Њ de tion (thyroid): CNS development/ function CNS development/ function and ?local neurotoxicity 2 toxicity ment/function (morphogenesis, ?proliferation) roid): CNS develop- ment/function de MR 2 2 Biological function(s) d Molecular- regulator tion: CNS develop- binding] phosphorylation): MR APPENDIX (Continued) no. category c ciency 275350 Transporter Transport (cofactor): None fi Clinical disorder resistance tion: endocrine func- dysmorphismsyndrome development/ function defects ment/function hormonogenesis V docrine function (thy- b c 1q Hypoparathyroidism- 604934 Chaperone Cytoskeleton (micro- fi ␤ Gene name arm te oxidase 12q Sulfocysteinuria 606887 Oxidoreductase Metabolic (amino acids): fi chaperone E retardation- tubule): ?CNS membrane 8 receptor aminotransferase ?MR 2 Translocase of inner Xq Mohr-Tranebjaerg 300356 Transporter Transport (mitochon- Teratocarcinoma-derived 3p Holoprosencephaly, 187395 Receptor Signaling pathway None Transcobalamin II 22q TC2 de Tubulin-speci Thyroglobulin 8q Genetic defect in thyroid 188450Thyroid Ligand hormone Hormone 3p synthesis: en- Thyroid hormone [ 190160 Receptor Transcription regula- TG-interacting factor 18p Holoprosencephaly 4 602630 Transcription Transcription regula- Tyrosine 16q Tyrosinemia type II 276600 Transferase Metabolic (amino acids): Sul Surfeit 1 9q Leigh syndrome 185620 [Protein Metabolic (oxidative ) growth factor 1 other forebrain (nodal): CNS develop- ) mitochondrial syndrome dria): metabolic; MR a DDP1 CRIPTO ( ( TIMM8A TDGF1 TC2 TBCE THRB TG TGIF TAT SUOX SURF1 Genesymbol Chr. OMIM function GO Drosophila FlyBase BLASTP 880 J. K. Inlow and L. L. Restifo ) h 43 88 22 44 113 151 148 Ϫ Ϫ Ϫ Ϫ -value Ϫ Ϫ Ϫ E continued ( g —— no. 0026317 0003738 , 0032075 f &) 0011828 * ( ) 0005198 (&) 0028993 ¶ (& (&) 0016650 homolog(s) isomerase scarecrow Fsh Tsc1 gigas Peroxidasin Triose phosphate Tetraspanin 29Fb e local energy Њ ciency ?and local fi CNS development/ function (thyroid): CNS devel- opment/function CNS development/ function ment/function (neu- ron/glia proliferation, differentiation) opment/function (neuron/glia prolifer- ation, differentiation) ment/function de toxicity cytoskeleton; ?CNS development/ function Biological function(s) d Molecular- ing protein G): CNS develop- APPENDIX (Continued) no. category c cation defect roid): CNS develop- fi ciency endocrine function: fi Clinical disorder hypothyroidism endocrine function: choreoathetosis opment/function de total iodideorgani docrine function (thy- b -chain ism due to TSHB (heterotrimeric G): ␤ Gene name arm hormone receptor hyperthyroidism, (heterotrimeric G): hormone, isomerase 1 hemolytic anemia MR 2 superfamily,member 2 transducer (integrin): ?actin others Thyroid transcription 14q Congenital 600635 Transcription Transcription regula- Thyroid-stimulating 14q Congenital 603372 Receptor Signaling pathway Thyroid-stimulating 1p Congenital hypothyroid- 188540 Ligand Signaling pathway None Tuberin 16p Tuberous sclerosis 2 191092 Receptor signal- Signaling pathway (small Hamartin 9q Tuberous sclerosis 1 605284 Protein binding Cytoskeleton: CNS devel- Thyroid peroxidase 2p Thyroid hormone or 606765 Oxidoreductase Hormone synthesis: en- Triosephosphate 12p Nonspherocytic 190450 Isomerase Metabolic (glycolysis): Transmembrane 4 Xq MRX58 300096 Signal Signaling pathway ) factor 1 hypothyroidism with factor tion: endocrine devel- a NKX2A ( TTF1 TSHR TSHB TSC2 TSC1 TPO TPI1 TM4SF2 Genesymbol Chr. OMIM function GO Drosophila FlyBase BLASTP Molecular Genetics of Mental Retardation 881 h / or he 83 17 50 30 ” 175 Ϫ Ϫ Ϫ Ϫ -value Ϫ E unknown hologs on “ ST score. open reading g no. gn ortholog status 0004832 selected from among MOCS2 ed by GO as ) 0014143 fi * cognitive impairment f “ ) 0036148 ¶ (&) 0003002 (& , others ( , others] 0028420 homolog(s) Kr-h1 odd paired Xpac CG6190 crocodile e (Table 3). ” were found by the OMIM search for development (cell fate, differentiation; morphogenesis) ?signaling pathway development/ function (neuron differentiation) development/ function (thyroid): CNS development/ function Biological function(s) ed only by genomic sequencing projects (see FlyBase at http:/ fi prime candidate “•••” “ d Molecular- APPENDIX (Continued) no. category c ) after an ortholog indicates that it is a ¶ Clinical disorder retardation syndrome ment/function; -value is shown. If two or more homologs are listed, only the exponent of the top-scoring BLASTP alignment is shown. For E b xes CG, BG, EG, ESTS, BEST, or BcDNA have been identi fi ” Gene name arm nger protein of 13q Holoprosencephaly 5 603073 Transcription Transcription nger homeobox 1B 2q Hirschsprung 605802 Transcription Transcription regula- [ ” fi fi ” cerebellum 2 factor regulation: CNS E3Atype A pigmentosum type A binding conjugating opment/function (proteasome): CNS Zinc- Xeroderma pigmentosum 9q Xeroderma 278700 Protein (DNA?) DNA repair: CNS devel- Zinc- Ubiquitin-protein ligase 15q Angelman syndrome 601623 Small protein Protein degradation Thyroid transcription 9q Congenital 602617 Transcription Transcription regula- secondary to. “ x FBgn before each accession number is required to access the entry in FlyBase. If two or more homologs are listed, only the FlyBase accession number of t fi ) factor 2 hypothyroidism factor tion: endocrine ) disease-mental regulator tion: CNS develop- a means Њ Alternative gene symbols used commonly in the literature are in parentheses.Bracketed Genes entries marked represent a proposed function, on the basis of the available literature, for genes that are not listed in GO or have been classi Only the exponent of the forward BLASTP The pre Mt indicates a gene in the mitochondrial genome. Additional disorders may also be caused by mutation of these genes. 2 SIP1 FOXE1 The Drosophila genes with pre The gene-sequencing software used by the Drosophila genome sequencing project (releases 2 and 3) has failed to recognize that homologs of both ( ( ?, precedes functionsa suggested but not conclusively demonstrated. b c d e f g h i ybase.bio.indiana.edu/ for details). An asterisk (*) following a gene name indicates a homolog that may be an ortholog, but it was not possible to assi learning disability. ZIC2 XPA ZFHX1B fl only on the basisthe of basis BLAST of reverse resultstwo BLAST and or analysis. functional more All domain other homologous alignments. Drosophila genes. Gene genes The names listed paragraph in are symbol orthologs. brackets ( The are ampersand homologous symbol to (&) the after human an gene, ortholog but indicates that are it not was likely to be ort UBE3A tRNA genes, the percentage identity, based on a pairwise alignment between the Drosophila and human sequences (using LALIGN), is shown in lieu of a BLA frames are present. TTF2 gene producing the top-scoring BLASTP alignment is given. “ molecular function. Genesymbol Chr. OMIM function GO Drosophila FlyBase BLASTP