MOLECULAR HETEROGENEITY OF AUTOSOMAL-DOMINANT CEREBELLAR-ATAXIA - ANALYSIS OF FLANKING MICROSATELLITES OF THE SPINOCEREBELLAR ATAXIA-1 LOCUS IN A NORTHERN EUROPEAN FAMILY UNEQUIVOCALLY DEMONSTRATES NON-LINKAGE

This study addresses the question whether the different forms of autos omal dominant cerebellar ataxia (ADCA) are related to different ethnic /geographical regions in Europe. One mutation in families originating from Holland, Prussia and Italy has previously been localized to chrom osome 6p (SCA1 locus), whereas the mutation in families of Iberic orig in has been excluded from chromosome 6p. In a Danish five-generation p edigree with ADCA and in which previous HLA-serotyping had shown incon clusive linkage results, the present study shows unequivocal exclusion from the SCA1 locus, firstly through the use of the new, highly infor mative microsatellites D6S89 and D6S109, which closely flank the SCAI locus, and secondly through the manifestation of disease in four pedig ree members previously scored as unaffected. Additional molecular gene tic analysis of the HLA DRbeta and F13A polymorphisms also argue again st a cluster of ADCA genes on chromosome 6p. Since this study demonstr ates the existence of non-SCA1 families and therefore heterogeneity in the North-European population, molecular family counselling remains r estricted to the few known SCA1 families.