Spinocerebellar ataxia type 2: polyQ repeat variation in the CACNA1A calcium channel modifies age of onset

Abstract

Nine neurodegenerative diseases, collectively referred to as polyglutamine (polyQ) diseases, are caused by expansion of a coding CAG DNA trinucleotide repeat. PolyQ diseases show a strong inverse correlation between CAG repeat length and age of disease onset (AO). Despite this, individuals with identical repeat expansion alleles can have highly variable disease onset indicating that other factors also influence AO. We examined AO in 148 individuals in 57 sibships from the SCA2 founder population in Cuba. The mutant CAG repeat allele explained 57% of AO variance. To estimate heritability of the residual variance after correction for SCA2 repeat length, we applied variance component analysis and determined the coefficient of intraclass correlation. We found that 55% of the residual AO variance was familial. To test candidate modifier alleles in this population, we selected 64 unrelated individuals from a set of 394 individuals who were highly discordant for AO after correction for SCA2 CAG repeat length. We hypothesized that long normal alleles in the other 8 polyQ disease genes were associated with premature disease onset in SCA2. Of the 8 genes tested, only long normal CAG repeats in the CACNA1A gene were associated with disease onset earlier than expected based on SCA2 CAG repeat size using non-parametric tests for alleles (P < 0.04) and genotypes (P < 0.023) after correction for multiple comparisons. CACNA1A variation explained 5.8% of the residual variation in AO. The CACNA1A calcium channel subunit represents an excellent candidate as a modifier of disease in SCA2. It is highly expressed in Purkinje cells (PCs) and is essential for the generation of the P/Q current and the complex spike in PCs. In contrast to other polyQ proteins, which are nuclear, the CACNA1A and SCA2 proteins are both cytoplasmic. Furthermore, small pathologic expansions of the polyQ domain in the CACNA1A protein lead to PC degeneration in SCA6. Future studies are needed to determine whether the modifier effect of CACNA1A relates to neuronal dysfunction or cell death of Purkinje neurons.

Normal-repeat-length polyglutamine peptides accelerate aggregation nucleation and cytotoxicity of expanded polyglutamine proteins

“…and L.M.T., unpublished data) while being protective in other cases (31,32). Likewise, the aggressiveness of an expanded polyGln disease might be stimulated by increases in concentration or repeat length of other polyGln disease proteins within the subcellular environment, as has recently been suggested by a genetics analysis of spinocerebellar ataxia 2 (33).…”

Molecular Pathogenesis of Spinocerebellar Ataxia Type 6

“…Third, clinical genetic studies point to a role played by the polyglutamine tract in the ␣1A subunit in modulating the severity of SCA2. 85 Specifically, SCA2 patients with larger normal, but not SCA6-causing, polyglutamine tracts in the ␣1A gene appear to have earlier onset ataxia than those with small ␣1A polyglutamine tracts.…”

Massive expansion of SCA2 with autonomic dysfunction, retinitis pigmentosa, and infantile spasms

“…8,9 There are reports of childhood-onset SCA2 with expansions of 62-75 repeats, 10 -13 and in some families variation in CACNA1A modifies age of onset. 14 Moderate-sized expansion in ATXN2 results in Purkinje cell degeneration through cellular dysfunction on multiple levels, [15][16][17] and may include abnormalities in RNA binding and splicing. 18 Mice with polyQ-58 mutations in Atxn2 have Purkinje cell degeneration similar to that seen in patients with adult-onset SCA2.…”