ANALYSIS OF THE DYNAMIC MUTATION IN THE SCA7 GENE SHOWS MARKED PARENTAL EFFECTS ON CAG REPEAT TRANSMISSION

The gene for spinocerebellar ataxia 7 (SCA7) includes a transcribed, t ranslated CAG tract that is expanded in SCA7 patients. We have determi ned expansions in 73 individuals from 17 SCA7 kindreds and compared th em with repeat lengths of 180 unaffected individuals. Subjects with ab normal expansions comprise 59 clinically affected individuals and 14 a t-risk currently unaffected individuals predicted to carry the mutatio n by haplotype analysis. For expanded alleles, CAG repeat length corre lates with disease progression and severity and correlates inversely w ith age of onset. Increased repeat lengths are seen in generational tr ansmission of the disease allele, consistent with the pattern of clini cal anticipation seen in these kindreds. Repeat lengths in expanded al leles show somatic mosaicism in leukocyte DNA, suggesting that these a lleles are unstable within individuals as well as between generations. Although dynamic repeat expansions from paternal transmissions are gr eater than those from maternal transmissions, maternal transmission of disease is more common, suggesting germline or embryonic effects of t he repeat expansion.