SOD1A4V-mediated ALS: Absence of a closely linked modifier gene and origination in Asia

Familial amyotrophic lateral sclerosis (ALS) accounts for 10% of all ALS. Approximately 20% of cases are due to mutations in the Cu/Zn superoxide dismutase gene (SOD1). In North America, SOD1A4V is the most common SOD1 mutation. Carriers of the SOD1A4V mutation share a common phenotype with rapid disease progression and death on average occurring at 1.4 years (versus 3–5 years with other dominant SOD1 mutations). Previous studies of SOD1A4V carriers identified a common haplotype around the SOD1 locus, suggesting a common founder for most SOD1A4V patients. In the current study we sequenced the entire common haplotypic region around SOD1 to test the hypothesis that polymorphisms in either previously undescribed coding regions or non-coding regions around SOD1 are responsible for the more aggressive phenotype in SOD1A4V–mediated ALS. We narrowed the conserved region around the SOD1 gene in SOD1A4V ALS to 2.8 Kb and identified five novel SNPs therein. None of these variants was specifically found in all SOD1A4V patients. It therefore appears likely that the aggressive nature of the SOD1A4V mutation is not a result of a modifying factor within the region around the SOD1 gene. Founder analysis estimates that the A4V mutation occurred 540 generations (∼12,000 years) ago (95% CI 480–700). The conserved minimal haplotype is statistically more similar to Asian than European population DNA sets, suggesting that the A4V mutation arose in native Asian–Americans who reached the Americas through the Bering Strait.