Multiple origins of the spinocerebellar ataxia 7 (SCA7) mutation revealed by linkage disequilibrium studies with closely flanking markers, including an intragenic polymorphism (G(3145)TG/A(3145)TG)

Spinocerebellar ataxia 7 (SCA7) is a neurodegenerative disease characterise d by the association of cerebellar ataxia and, in most patients, progressiv e macular degeneration leading to loss of autonomy and blindness. The patie nts die after 5-30 years of evolution. The cause of the disease has been id entified as a (CAG)(n) repeat expansion in the coding sequence of the SCA7 gene on chromosome 3p. De novo mutations occur on intermediate-sized allele s carrying from 28 to 35 CAG repeats. Neomutations explain the persistence of the disease in spite of the great instability of the repeat sequence whi ch results in the appearance of juvenile onset patients and the extinction of the disease within families. This rare disorder has been reported in a w ide variety of countries and ethnic groups. In a large number of SCA7 famil ies (n = 41) of different origins, we have determined the haplotypes segreg ating with the mutation of several microsatellite markers close to the SCA7 gene and of a new intragenic polymorphism (G(3145)TG/A(3145)TG). Four diff erent haplotypes were found for centromeric markers (G(3145)TG/A(3145)TG-D3 S1287-D3S3635) in the majority of the kindreds from four different geograph ic regions: A-2-4 in Korea; A-3-6 in North Africa, B-3-6 in continental Eur ope and A-4-6 in the UK and USA. The haplotypes in the Jamaican, Filipino, Brazilian and German families were different, suggesting that independent r egional founders are at the origin of the SCA7 mutation in each population. Two different haplotypes were observed, however, in two families from the same rural area in central Italy in which de novo SCA7 mutations on interme diate alleles have been observed, suggesting the existence of different poo ls of at-risk chromosomes in this population.