High germinal instability of the (CTG)(n) at the SCA8 locus of both expanded and normal alleles

The autosomal dominant spinocerebellar ataxias (SCAs) are a group of late-o nset, neurodegenerative disorders for which 10 loci have been mapped (SCA1, SCA2, SCA4-SCA8, SCA10, MJD, and DRPLA). The mutant proteins have shown an expanded polyglutamine tract in SCA1, SCA2, MJD/SCA3, SCA6, SCA7, and DRPL A; a glycine-to-arginine substitution was found in SCA6 as well. Recently, an untranslated (CTG), expansion on chromosome 13q was described as being t he cause of SCA8. We have now (1) assessed the repeat size in a group of pa tients with ataxia and a large number of controls, (2) examined the interge nerational transmission of the repeat, and (3) estimated the instability of repeat size in the sperm of one patient and two healthy controls. Normal S CA8 chromosomes showed an apparently trimodal distribution, with classes of small (15-21 CTGs), intermediate (22-37 CTGs), and large (40-91 CTGs) alle les; large alleles accounted for only0.7% of all normal-size alleles. No ex panded alleles (greater than or equal to 100 CTGs) were found in controls. Expansion of the CTC; tract was found in five families with ataxia; expande d alleles (all paternally transmitted) were characterized mostly by repeat- size contraction. There was a high germinal instability of both expanded an d normal alleles: in one patient, the expanded allele (152 CTGs) had mostly contraction in size (often into the normal range); in the sperm of two nor mal controls, contractions were also more frequent, but occasional expansio ns into the upper limit of the normal size range were also seen. In conclus ion, our results show (1) no overlapping between control (15-91) and pathog enic (100-152) alleles and (2) a high instability in spermatogenesis (both for expanded and normal alleles), suggesting a high mutational rate at the SCA8 locus.