Genetic mutation, linkage and heterogeneity analysis in Spanish pedigrees and isolated cases of autosomal dominant spinocerebellar ataxia (SCA)
1994
We report a genetic study of 14 Spanish kindreds and 11 isolated cases with SCA. The diagnosis was ascertained in 60 members, but clinical data were only obtained for 35 of them. One defective gene responsible for the disease was localized to 6p22-p23 (SCA1) and the mutation consists of an expansion of an intragenic (CAG){sub n} repeat (REP). We studied all of our genealogical and isolated affected individuals in order to know their 6p mutational status. Thus we detected a large pedigree which has the pathological expansion with {open_quotes}n{close_quotes} in the range of 41 to 57 repeats. The expansion increases through generations and correlates with anticipation. In the Spanish population, the non-pathological range of {open_quotes}n{close_quotes} is from 6 to 39 repeats. These sequences are {open_quotes}protected{close_quotes} having an interrupted repeat configuration, studied by restriction and sequencing analysis. This mutation was not present in the genealogical or isolated affected individuals studied. We also tested our families with the recently reported CAG expansion in 12p-12ter (DRPLA) and obtained negative results. Linkage analysis in non-SCA1, DRPLA families using markers from others chromosomal regions, 12q23-24.1 (SCA2) and 14q24.3-q32 (SCA3), results in negative lod scores and shows genetic heterogeneity in our population.
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