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

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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.