TRACING AN ANCESTRAL MUTATION - GENEALOGICAL AND HAPLOTYPE ANALYSIS OF THE INFANTILE ONSET SPINOCEREBELLAR ATAXIA LOCUS

Infantile onset spinocerebellar ataxia (IOSCA) is a progressive neurol ogical syndrome exhibiting an autosomal recessive pattern of inheritan ce. The characteristic features were described in Finland in the begin ning of 1990s. Having shown that IOSCA does not segregate With any of the markers linked to other hereditary ataxias and thus represents a g enetically distinct disease, we assigned the locus of this new heredit ary ataxia to 10q23.3-q24.1. To approximate the age of the Finnish IOS CA mutation and to investigate the possible existence of more than one mutation underlying the disease, the ancestors of 13 IOSCA families w ere identified by use of church records dating back to the 1500s. The IOSCA pedigrees were frequently merged, providing support for these ha ving one common ancestor. Analysis of the extended IOSCA haplotypes ex posed ancient recombination events and revealed one core haplotype of four markers on a region of similar to 2 cM, which was unequivocally p resent in 92% of disease chromosomes. Both genealogical and haplotype data thus suggest that a single IOSCA ancestral mutation was introduce d into the Finnish population most probably similar to 30-40 generatio ns ago before the time when the general east-west migration took place within Finland.