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5. Triplet Repeats 248. A Abstracts S101 provide no support for the hypothesis that variation at the polymorphism in the hSKCa3 gene, in patients with anor- COMT gene influences susceptibility to bipolar disorder. exia nervosa (AN). AN is characterized by profound weight loss, body image disturbances and intense fear of obesity and is frequently associated with mood and anxi- 5. Triplet Repeats ety disorders. Familial and twin studies suggest the involvement of inherited genetic factors in the etiology of AN. 246. EXPANDED TRINUCLEOTIDE REPEATS IN We assessed 25 AN patients and their non-affected EARLY ONSET PATIENTS WITH PSYCHOSIS. Davies parents. PCR was used to amplify fragments MA*, Gombrich M, Kennedy JL, Vincent JB and Schulz encompassing two stretches of polymorphic CAG repeats SC. *Department of Psychiatry, Case Western Reserve in the hSKCa3 gene and the products were separated on University, Ohio. a 6% denaturing polyacrylamide gels. An analysis of Expansion in trinucleotide repeat sequences occurs in alleles in the parents and affected offspring revealed that several neurogenetic diseases including fragile X syn- no expansion took place and that there was no preferential drome, myotonic dystrophy and Kennedy’s disease. transmission of longer hSKCa3 alelles. The preliminary Unstable DNA sequences represent a type of DNA results of our study do not support the hypothesis that the mutation which is characterized by quantitative changes variable length of CAG repeats in the hSKCa3 gene are in an individual genotype and, in some diseases, vari- involved in the genetic susceptibility to anorexia nervosa. ations in phenotypic expression. Unstable DNA is also a biological bases for genetic anticipation (characterized by progressively earlier age at onset and/or increasing sever- 248. A NOVEL CAG TRINUCLEOTIDE REPEAT ity of illness in successive generations). While antici- EXPANSION IN THE 5Ј REGION OF A GENE ENCODING pation has been of interest in the etiology of psychotic A SUBUNIT OF PROTEIN PHOSPHATASE 2A IS ASSO- illnesses, recent studies are inconsistent in their results. CIATED WITH A PROGRESSIVE NEUROPSYCHIATRIC Specific Aims: Using the technique repeat expansion DISORDER. Holmes SE1,. O’Hearn E2,3, McInnis MG1, detection (RED), we have analyzed genomic DNA from Kwak NG1, Gorelick-Feldman DA1, Kleiderlein JK1, Calla- early-onset (prior to age 20) psychiatric patients with psy- han C1, Sherr M1, Sharp AH1, Sumner AJ4, Ashworth RG5, chotic illnesses and compared them to controls matched Ananth U6, Seltzer W6, Vieria-Saecker AM7, Epplen JT7, for age, sex and ethnicity. Our hypothesis was: There Reiss O8, Ross CA1,3, Margolis RL1.. 1Dept. of Psychiatry, would be a significant difference between the CAG/CTG 2Dept. of Neurol., 3Dept. of Neurosci., 5Inst. Med. Genet., trinucleotide repeat sizes in the patients vs. controls. Johns Hopkins U. Sch. of Med., Baltimore, MD 21287; Results: To date, we have analyzed data on 37 matched 4Dept. of Neurol., Louisiana State U. Sch. of Med.; pairs and have found no significant differences in 6Athena Diagnostics; 7Dept. Med Genetics and Neurology, CAG/CTG repeat sizes when we compared all affecteds Ruhr-University, 8Dept. Med. Genet., U. of Rostock. with controls. However, for patients with bipolar illness, We have ascertained a large family (pedigree R) with it was notable that the data showed that 2 of 12 affecteds a progressive autosomal dominant disorder with a vari- (12.5%) had nine or more ligation products compared to able age of onset. The phenotype, also variable, includes controls (0%). This difference in larger ligations products tremor, ataxia, cerebellar and basal ganglia signs, and was not found for patients with schizophrenia. However, dementia. An expansion of a CAG trinucleotide repeat in 18 schizophrenic individuals (86%) seemed to cluster in genomic DNA of affected individuals was detected with the smaller ligation products (6 or less) compared to con- RED (repeat expansion detection). All known CAG expan- trols (52%). sions were excluded, including SCA8. A segment of gen- omic DNA containing the repeat was cloned, and a PCR assay of repeat length was developed. The repeat is 247. ASSOCIATION ANALYSIS OF CAG REPEATS located 5’ to the putative first exon of a regulatory subunit WITHIN hSKCa3 CHANNEL GENE WITH ANOREXIA of protein phosphatase 2A. The repeat is 7 to 28 triplets NERVOSA IN FAMILY TRIOS. 1,5Gak E, 2,5Frisch A, in length in control populations, with a heterozygosity of 2,5Michaelovsky E, 3,5Laufer N, 4Danziger J, 3,5Apter A, 60%. Affected individuals in pedigree R, but not unaffec- 1Gutin E, 1,5Koronyo-Hamaoui M, 1,5Barkai G, 1,5Goldman ted family members older than age 60, have an expanded B, 3,5Weizman A.. 1Sheba Medical Center, 2Felsenstein repeat Ͼ65 triplets (lod = 3.81 at theta = 0). We hypothes- Medical Research Center, 3Geha Hospital, 4Schneider ize that this repeat expansion is the mutation responsible Children’s Hospital, 5Sackler Faculty of Medicine, Tel for the hereditary neurological disorder in pedigree R. Aviv Univ., Israel. This work was supported in part by the Huntington’s Dis- Association of expanding trinucleotide repeats and ease Society of American, NS16375, MH01275, and major psychiatric disorders, including schizophrenia, MH50763. mood disorder and autism, have been investigated recently. To explain these common, highly heterogeneous and complex disorders by a unified molecular mech- 249. ASSOCIATION ANALYSIS OF DI- AND TRINU- anism, is appealing, especially in view of the phenotypic CLEOTIDE REPEAT POLYMORPHISMS IN THE REGU- overlap between diagnostic entities. The hSKCa3 potass- LATORY REGIONS OF THE HUMAN PAX-3 AND PAX- ium channel, involved in regulating neuronal activity, is 7 GENES WITH PSYCHIATRIC DISORDERS. Syagailo YV, a natural candidate for investigation. Mild alterations in Okladnova O, Sto¨ber G, Reimer E, Tranitz M, Meyer J, length of trinucleotide repeats within this gene were Lesch K-P. Department of Psychiatry, University of found to be associated, although not inconsistently, with Wuerzburg, Fuechsleinstr.15, D-97080 Wuerzburg, Ger- schizophrenia and bipolar disorders. To test the hypoth- many. esis of a common underlying genetic mechanism for psy- The paralogous genes Pax-3 and Pax-7 are members chiatric disorders, we investigated the trinucleotide repeat of the Pax multigene family of transcription factors, which Abstracts S102 are involved in the early regionalization of the embyo alone SCA8. “Super” expansions at TGC13–7a/SCA8 may brain and may play a role in the differentiation, mainte- be allelic variants that predispose to psychosis via a differ- nance, and functional assembly of specific subsets of cells ent molecular mechanism compared to the more modest in the adult brain. We have isolated and characterized the expansion alleles reported for SCA8. Alternatively this 5Ј flanking regions of both genes. In the PAX-3 gene, a expansion may be completely unrelated to psychosis. polymorphic (CA)13–31 repeat was found at nt position − 337. The (CA)25 variant confers a significantly lower tran- scriptional efficiency on the PAX-3 gene promoter. In the 251. ISOLATION OF GENES CONTAINING TRINUCLE- PAX-7 gene promoter, a polymorphic (CCT)8–11 repeat OTIDE REPEAT EXPANSION. Yuan QP, Lindblad K, sequence is located directly upstream of the proximal start Schalling M.. Neurogenetics Unit, Center for Molecular site. In cell transfection assays with the PAX-7 gene pro- Medicine, Karolinska Hospital, 17176 Stockholm, Swed- moter, no differences in transcriptional efficiency between en. different alleles were found. Previously, a contribution of Anticipation, an increase of disease severity and polymorphic repeats in brain expressed genes to behav- decrease of age-of-onset in successive generations within ioural and personality differences among individuals have a family, is a hallmark of trinucleotide repeat disorders. been reported; therefor, we have genotyped a sample of Independent studies have reported evidence of antici- patients with psychiatric disorders for the gene variants pation in psychiatric disorders, e.g. bipolar affective dis- described here. A moderately lower abundance order and schizophrenia, suggesting the involvement of (Wilcoxon’s test: p=0.02) was found for the the PAX-3 pro- triplet repeat in the ctiology of disease. We have moter 25 repeat allele in a sample of the paranoid subtype developed an isolation strategy for DNA fragments con- of schizophrenia (ෂ9%; n=164 alleles) compared to a con- taining enlarged repeat sequences. Sucrose gradient and trol sample (ෂ16%; n=444 alleles), but not with other psy- denaturing gradient gel electrophoresis (DGGE) or agarose chiatric disorders (other schizophrenia subtypes: n=382 gel electrophoresis are used to enrich the target fragments alleles, affective disorders: n=292 alleles). from digested genomic DNA. The enriched DNA frag- Compared to our previous findings for the PAX-6 pro- ments are then cloned into Zap-Express vector to isolate moter repeats, the PAX-3/PAX-7 variants described here the single clones carrying the expanded repeat sequence. seem to be of limited importance for the genesis of psychi- The repeat expansion detection (RED) method is used to atric disorders. follow the repeat throughout the whole procedure. Strin- gent hybridization conditions enabled us to isolate single clones containing long repeat sequences. This isolation 250. TRINUCLEOTIDE REPEAT FOR SCA8 ON 13q21: strategy has been applied to the cloning of long repeat “SUPER” EXPANSION IN PSYCHOTIC INDIVIDUALS containing
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