EVIDENCE FOR A MECHANISM PREDISPOSING TO INTERGENERATIONAL CAG REPEATINSTABILITY IN SPINOCEREBELLAR ATAXIA TYPE-I

Spinocerebellar ataxia type I (SCAI) is an autosomal dominant neurodeg enerative disease caused by the expansion of a CAG trinucleotide repea t on chromosome 6p. Normal alleles range from 19-36 repeats while SCA1 alleles contain 43-81 repeats. We now show that in 63% of paternal tr ansmissions, an increase in repeat number is observed, whereas 69% of maternal transmissions showed no change or a decrease in repeat number . Sequence analysis of the repeat from 126 chromosomes reveals an inte rrupted repeat configuration in 98% of the unexpanded alleles but a co ntiguous repeat (CAG)n configuration in 30 expanded alleles from seven SCA1 families. This indicates that the repeat instability in SCA1 is more complex than a simple variation in repeat number and that the los s of an interruption predisposes the SCA1 (CAG)n to expansion.