Spinocerebellar ataxia type 2: polyQ repeatvariation in the CACNA1A calciumchannel modifies age of onset

ABSTRACT

Nine neurodegenerative diseases, collectively referred to as polyglutamine (polyQ) diseases, are caused byexpansion of a coding CAG DNA trinucleotide repeat. PolyQ diseases show a strong inverse correlationbetween CAG repeat length and age of disease onset (AO). Despite this, individuals with identical repeatexpansion alleles can have highly variable disease onset indicating that other factors also influence AO. Weexamined AO in 148 individuals in 57 sibships from the SCA2 founder population in Cuba. The mutant CAGrepeat allele explained 57 percent of AO variance. To estimate heritability of the residual variance after correction forSCA2 repeat length, we applied variance component analysis and determined the coefficient of intraclasscorrelation. We found that 55 percent of the residual AO variance was familial. To test candidate modifier allelesin this population, we selected 64 unrelated individuals from a set of 394 individuals who were highly discordantfor AO after correction for SCA2 CAG repeat length. We hypothesized that long normal alleles in the other8 polyQ disease genes were associated with premature disease onset in SCA2. Of the 8 genes tested, only longnormal CAG repeats in the CACNA1A gene were associated with disease onset earlier than expected basedon SCA2 CAG repeat size using...(AU)