| Project/Area Number |
22590923
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Neurology
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| Research Institution | The University of Tokyo |
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Principal Investigator |
TAKAHASHI Yuji 東京大学, 医学部附属病院, 助教 (00372392)
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| Project Period (FY) |
2010 – 2012
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| Project Status |
Completed (Fiscal Year 2012)
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| Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2012: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2011: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2010: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
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| Keywords | 脳神経疾患 / 遺伝子 / ゲノム / 筋萎縮性側索硬化症 / 連鎖解析 / エクソーム解析 / ゲノム解析 / ALS / 変異解析 |
|---|
| Research Abstract |
This study aims for the identification of causative genes in autosomal-recessive familial amyotrophic lateral sclerosis (AR-FALS) through a linkage analysis and mutational analysis of genes located in the candidate regions. A homozygosity mapping of three AR-FALS pedigrees revealed a candidate region overlapped among all the pedigrees. Specific primers for genomic PCR were designed for all the exons of 40 genes located in the candidate region. In addition, an array comparative genomic hybridization (array-CGH) system was designed for the detection of copy-number variations. Mutational analysis employing these systems, however, did not reveal a novel mutation. Then, a linkage analysis with the assumption of autosomal recessive mode of inheritance allowing compound heterozygous mutations was performed in one of the pedigrees with the largest pedigree size, which revealed candidate regions spanning a total length of 470 mega-bases. An exome analysis and a whole genome sequencing con ducted for a proband in the pedigree revealed an novel nonsynonymous homozygous mutation which was not registered in public databases including dbSNP, NHL-ESP or 1000 genomes. The mutation was co-segregated among family members and not found in 461 Japanese controls. Mutational analysis for 20 FALS pedigrees in whom mutations in known causative genes were excluded, however, did not reveal homozygous or compound heterozygous mutations in the gene. Mutational analysis for additional FALS pedigrees was considered to be necessary to establish the pathogenicity of the identified mutation.
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