Identification of a causative gene for autosomal recessive familial amyotrophic lateral sclerosis

2012 Fiscal Year Final Research Report

• Project/Area Number: 22590923
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurology
• Research Institution: The University of Tokyo
• Principal Investigator: TAKAHASHI Yuji 東京大学, 医学部附属病院, 助教 (00372392)
• Project Period (FY): 2010 – 2012
• Keywords: 脳神経疾患 / 遺伝子 / ゲノム

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.

Research Products

• [Presentation] Exome analysis for early-onset amyotrophic lateral sclerosis with autosomal recessive mode of inheritance. (2012)
  • Author(s): Yuji Takahashi, Koichiro Higasa, Satoshi Takagi, Tadashi Kurita, Hiroyuki Ishiura, Jun Mitsui, Yoko Fukuda, Jun Yoshimura, Taro L. Saito, Shinichi Morishita, Jun Goto and Shoji Tsuji.
  • Organizer: The 62nd American Society of Human Genetics Annual Meeting
  • Place of Presentation: San Francisco, USA
  • Year and Date: 20120000