Molecular features of the CAG repeats of spinocerebellar ataxia 6 (SCA6)

Department of General Internal Medicine, Hiroshima University, Hirosima, Hiroshima, Japan
Human Molecular Genetics (Impact Factor: 6.39). 08/1997; 6(8):1283-7. DOI: 10.1093/hmg/6.8.1283
Source: PubMed


Spinocerebellar ataxia 6 (SCA6) is an autosomal dominant spinocerebellar degeneration caused by the expansion of the polymorphic CAG repeat in the human alpha1A voltage-dependent calcium channel subunit gene (CACNL1A4 gene). We have analyzed 60 SCA6 individuals from 39 independent SCA6 Japanese families and found that the CAG repeat length is inversely correlated with the age of onset (n = 58, r = -0.51, P < 0.0001). SCA6 chromosomes contained 21-30 repeat units, whereas normal chromosomes displayed 6-17 repeats. There was no overlap between the normal and affected CAG repeat number. The anticipation of the disease was observed clinically in all eight parent-child pairs that we examined; the mean age of onset was significantly lower (P = 0.0042) in children than in parents. However, a parent-child analysis showed the increase in the expansion of CAG repeats only in one pair and no diminution in any affected cases. This result suggests that factors other than CAG repeats may produce the clinical anticipation. A homozygotic case could not demonstrate an unequivocal gene dosage effect on the age of onset.

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Available from: Yuishin Izumi, Sep 19, 2015
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    • "SCA3 Standard PCR Kawaguchi et al., 1994 160bp þ 3n (n ¼ number of CAG repeats). SCA6 Standard PCR Matsuyama et al., 1997 102bp þ 3n (n ¼ number of CAG repeats). SCA7 Standard PCR David et al., 1997 272bp þ 3n (n ¼ number of CAG repeats). "
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    • "As the mutation of SCA6 is in CACNA1A encoding Cav2.1, a pore-forming subunit of P/Q-type voltage-dependent calcium channel essential for neurons [4, 30, 55], it is possible that such small polyQ expansion leads to neurodegeneration by functional alterations of Cav2.1 [5, 14, 21, 28, 35, 36, 50]. However, two recent studies on different SCA6 knock-in mice neither found that expanded polyQ affects the electrophysiological properties of Cav2.1 [37, 57], suggesting that the pathogenic mechanism of polyQ expansion in SCA6 is not merely due to functional changes of Cav2.1. "
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