MACHADO-JOSEPH-DISEASE IN PEDIGREES OF AZOREAN DESCENT IS LINKED TO CHROMOSOME-14

A locus for Machado-Joseph disease (MJD) has recently been mapped to a 30-cM region of chromosome 14q in five pedigrees of Japanese descent. MJD is a clinically pleomorphic neurodegenerative disease that was or iginally described in subjects of Azorean descent. In light of the non allelic heterogeneity in other inherited spinocerebellar ataxias, we w ere interested to determine if the MJD phenotype in Japanese and Azore an pedigrees arose from mutations at the same locus. We provide eviden ce that MJD in five pedigrees of Azorean descent is also linked to chr omosome 14q in an 18-cM region between the markers D14S67 and AACT (mu ltipoint lod score +7.00 near D14S81). We also report molecular eviden ce for homozygosity at the MJD locus in an MJD-affected subject with s evere, early-onset symptoms. These observations confirm the initial re port of linkage of MJD to chromosome 14; suggest that MJD in Japanese and Azorean subjects may represent allelic or identical mutations at t he same locus; and provide one possible explanation (MJD gene dosage) for the observed phenotypic heterogeneity in this disease.