Molecular analysis of a de novo mutation for spinocerebellar ataxia type 6and (CAG)n repeat units in normal elder controls

Spinocerebellar ataxia type 6 (SCA6) is an autosomal dominant spinocerebell ar degenerative disease caused by CAG repeat expansions in the human alpha( 1A) voltage-dependent calcium channel subunit gene (CACNL1A4). We analyzed 15 SCAB patients in 14 unrelated Japanese families and 52 healthy Japanese aged over 74 years. Sequence analysis was performed to determine the correc t number of CAG repeats. The expanded CAG repeat number was 23.6+/-2.1 (mea n+/-S.D., n=15) with a range of 20-29, and the shortest expanded allele was 20 repeats. Moreover, the analysis of normal subjects revealed that the CA G repeat number of normal alleles was 12.3+/-1.9 (n=104) with a range of 7- 18. We concluded that the normal range of CAG repeats in the CACNL1A4 gene is 18 or less, and that the disease range is 20 or more. Of 15 SCAB patient s, three sporadic cases were observed. In one male patient with 26 CAG repe ats, the CAG repeat numbers of his parents were within normal range. His ex panded allele was considered to be caused by an expansion of a normal allel e from his mother (14 or 17 repeats). This is the first SCAB case which was genetically proven to occur due to a de novo mechanism, suggesting that la rger CAG repeats of normal alleles in the CACNL1A4 gene may be unstable and result in full expansion. (C) 1998 Elsevier Science B.V. All rights reserv ed.