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

Spinocerebellar ataxia 6 (SCA6) is an autosomal dominant spinocerebellardegeneration caused by the expansion of the polymorphic CAG repeat in thehuman alpha1A voltage-dependent calcium channel subunit gene (CACNL1A4gene). We have analyzed 60 SCA6 individuals from 39 independent SCA6Japanese families and found that the CAG repeat length is inverselycorrelated with the age of onset (n = 58, r = - 0.51, P < 0.0001). SCA6chromosomes contained 21-30 repeat units, whereas normal chromosomesdisplayed 6-17 repeats. There was no overlap between the normal andaffected CAG repeat number. The anticipation of the disease was observedclinically in all eight parent-child pairs that we examined; the mean ageof onset was significantly lower (P = 0.0042) in children than in parents.However, a parent-child analysis showed the increase in the expansion ofCAG repeats only in one pair and no diminution in any affected cases. Thisresult suggests that factors other than CAG repeats may produce theclinical anticipation. A homozygotic case could not demonstrate anunequivocal gene dosage effect on the age of onset.