| Budget Amount *help |
¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 2003: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2002: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Research Abstract |
1)Male embryonic mice with mutations in the X-linked aristaless-related homeobox gene(ARX) developed with small brains due to suppressed proliferation and regional deficiencies in the forebrain. These mice also showed aberrant migration and differentiation of interneurons containing GABAergic intercneurons in the ganglionic eminence and neocortex as well as abnormal testicular differentiations. These characteristics recapitulate some of the clinical features of X-linked lissencephaly with abnormal genitalia(XLAG) in humans. We found multiple loss pf function mutations in ARX individuals affected XLAG and some female relatives, and conclude that mutations of ARX caused XLAG. The present report, to our knowledge the first to use phenotypic analysis of a knockout mouse to identify a gene associated with an X-linked human brain malformation.
2)Rett syndrome(RTT) is an X-linked dominant neurodeveloprnental disorder characterized by cognitive and adapted regression with autistic behavior, ste
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reotypical hand movements, epilepsy and ataxia. Over 120 different mutations in the nmethyl-CpG binding protein 2 gene(MECP2) have been reported in patients with RTT, but a genotype-phenotype correlation has not been established. We have studied MECP2 mutations in 221 Japanese sporadic patients diagnosed clinically to having RTT and 40 different mutations in MECP2 have been detected in 146 patients. Common mutations were four missense mutations, T158M,P152R,R133C and R306C) observed in 40 cases and four nonsense mutations(R168X,R255X,R20X,R294) were detected in 38 cases. Comparing phenotypes in patients with common mutations, three mutations 8R133C,R306C and R294X were more frequently detected in patients with atypical RTT including preserved speech variant type. On the other hand, patients with T1q58M and R168X mutations have typical clinical features of RTT. These results suggest that there is a genotype-phenotype correlation of MECP2 in patients with RTT, although a large scale study of adult patients with RTT needs to determine more precise influence of mutation type in MECP2.
3)We identified a novel giant gene encoding a transmembrane protein with cub and sushi multiple domains on the human chromosome 8q23.3\q24.1.in which benign adult familial myoclonus epilepsy type 1(BAFAMME/FAME, Omim:601068} has been mapped. This giant gene consists of 73 exons and spans over 1.2Mb on the genomic DNA regions. It showed significant homology to two genes, CSMD1 gene on 8p23 and CSMD2 gene on 1p34, at reduced amino acid sequence level and hence we designated as CSMD3. The CSMD3 gene was expressed mainly in adult and fetal brains. We performed mutation analysis on the CSMD3 gene for seven patients with BAFME1/FAM, but no mutation was found in the coding sequence of the CSMD3 gene. Less
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