CAG repeat length in RAI1 is associated with age at onset variability in spinocerebellar ataxia type 2 (SCA2).
Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant disorder caused by the expansion of a polymorphic (CAG)(n) tract, which is translated into an expanded polyglutamine tract in the ataxin-2 protein. Although repeat length and age at disease onset are inversely related, approximately 50% of the age at onset variance in SCA2 remains unexplained. Other familial factors have been proposed to account for at least part of this remaining variance in the polyglutamine dis-orders. The ability of polyglutamine tracts to interact with each other, as well as the presence of intra-nuclear inclusions in other polyglutamine disorders, led us to hypothesize that other CAG-containing proteins may interact with expanded ataxin-2 and affect the rate of protein accumulation, and thus influence age at onset. To test this hypothesis, we used step-wise multiple linear regression to examine 10 CAG-containing genes for possible influences on SCA2 age at onset. One locus, RAI1, contributed an additional 4.1% of the variance in SCA2 age at onset after accounting for the effect of the SCA2 expanded repeat. This locus was further studied in SCA3/Machado-Joseph disease (MJD), but did not have an effect on SCA3/MJD age at onset. This result implicates RAI1 as a possible contributor to SCA2 neurodegeneration and raises the possibility that other CAG-containing proteins may play a role in the pathogenesis of other polyglutamine disorders.
Department of Biology, Centre for Research in Neurosciences and Douglas Hospital Research Institute, McGill University, Montreal, Quebec H3G 1A4, Canada.
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Hayes
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Turecki
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Brisebois
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Lopes-Cendes
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Gaspar
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Riess
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Ranum
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Pulst
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Rouleau
D017668:Age of Onset; D000483:Alleles; D000067528:Ataxins; D006801:Humans; D009419:Nerve Tissue Proteins; D015221:Potassium Channels / Q000235:genetics; D024681:Potassium Channels, Calcium-Activated; D011506:Proteins / Q000235:genetics*; D051640:Small-Conductance Calcium-Activated Potassium Channels; D020754:Spinocerebellar Ataxias / Q000235:genetics*; D018911:Trinucleotide Repeats
D000067528:Ataxins; C406328:KCNN3 protein, human; D009419:Nerve Tissue Proteins; D015221:Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D011506:Proteins; D051640:Small-Conductance Calcium-Activated Potassium Channels