Screening for rare variants in the coding region of ALS-associated genes at 9p21.2 and 19p13.3

• Published in: Neurobiology of aging 2013-05, Vol.34 (5), p.1518.e5-1518.e7
• Main Authors: Koppers, Max, Groen, Ewout J.N, van Vught, Paul W.J, van Rheenen, Wouter, Witteveen, Esther, van Es, Michael A, Pasterkamp, R. Jeroen, van den Berg, Leonard H, Veldink, Jan H
• Format: Article
• Language: English
• Subjects: Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - epidemiology; Amyotrophic Lateral Sclerosis - genetics; C9ORF72; Chromosomes, Human, Pair 19 - genetics; Chromosomes, Human, Pair 9 - genetics; Female; Genetic Markers - genetics; Genetic Predisposition to Disease - epidemiology; Genetic Predisposition to Disease - genetics; Genetic Testing - statistics & numerical data; Genetic Variation - genetics; Genetics; Genome-wide association studies; Humans; Internal Medicine; Male; Mutation analysis; Netherlands - epidemiology; Neurology; Prevalence; Risk Factors; UNC13A
• ISSN: 0197-4580; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2012.09.018

Abstract Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease that causes progressive muscle weakness, eventually resulting in death because of respiratory failure. Genetic variants are thought to predispose to the disease. A recent, large, genome-wide association study identified 2 loci that increase susceptibility to ALS. These 2 loci on chromosomes 9 and 19 consist of 4 genes: UNC13a , IFNK , MOBKL2b , and C9ORF72 . A hexanucleotide repeat expansion in the noncoding region of C9ORF72 was recently identified as the cause of chromosome 9-linked ALS-FTD (frontotemporal dementia). In this study, our aim was to determine whether the coding regions of these genes harbor rare, nonsynonymous variants that play a role in ALS pathogenesis. In DNA from 1019 sporadic ALS patients and 1103 control subjects of Dutch descent, we performed a mutation screening analysis in the coding region of these 4 genes by resequencing the exons. A total of 16 amino acid-changing rare variations were identified, 11 in UNC13a and 5 on chromosome 9. Some of these were unique to ALS, but were detected in a single patient. None of the genes showed significant enrichment of rare variants in the coding sequence. Rare variants in the coding region of UNC13a , IFNK , MOBKL2b , and C9ORF72 are unlikely to be a genetic cause of ALS.