Brain Advance Access originally published online on July 6, 2005
Brain 2005 128(10):2297-2303; doi:10.1093/brain/awh586
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Spinocerebellar ataxia type 2: polyQ repeat variation in the CACNA1A calcium channel modifies age of onset
1 Division of Neurology and Rose Moss Laboratory for Parkinson and Related Diseases, Burns and Allen Research Institute, Cedars-Sinai Medical Center, 2 Department of Medicine, 3 Department of Neurobiology, 4 Department of Pediatrics and 5 Department of Epidemiology, CSMC, Medical Genetics Institute, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA and 6 Clínica para la Investigación y Rehabilitación de las Ataxias Hereditarias, Holguín, Cuba
Corresponding author: Dr Stefan-M. Pulst, Division of Neurology, Cedars-Sinai Medical Center, Department of Medicine and Department of Neurobiology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90048, USA E-mail: Pulst{at}CSHS.org
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.
Key Words: spinocerebellar ataxia type 2 (SCA2); age of disease onset, heritability; genetic modifier; CACNA1A; spinocerebellar ataxia type 6 (SCA6)
Abbreviations: AO = age of onset; PC = Purkinje cell; polyQ = polyglutamine
Received March 28, 2005. Revised May 27, 2005. Accepted June 9, 2005.
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