Mapping of the gene for Holmes' ataxia by searching of triplet repeats

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Holmes' ataxia is one of the most popular spinocerebellar ataxia in the Japanese. The number of patients exceeds 30 % among ataxic patients. Although recent advances in molecular genetics have revealed 7 different genes for spinocerebellar ataxia, named as SCAl to SCA7, the gene for Holmes' ataxia remains unknown. The purpose of this project is to identify the responsible gene for Holmes's ataxia by linkage analysis. Since weak genetic anticipation is observed in this disease, abnormal expansions of the CAG trunucleotide repeat is suggested as gene abnormality. At first we have made a comparison between Holmes' ataxia and known hereditary ataxia, then we have found followings ;1) The responsible gene for the half of the patients with Holmes's ataxia in the Japanese are identical to that of SCA6.2) The responsible gene for SCA6 is a gene for alpha lA - voltage dependent calcium channel (CACNLlA4) mapped at 19p13.3) An abnormal expansions of the CAG trunucleotide repeat located in the CACNL1A4 was observed in the patients with SCA6.4) The number of CAG repeat inversely correlated with age of onset.5) Strong linkage disequilibrium suggested that SCA6 in the Japanese in Hokkaido may derive from a single common ancestry.It should be solved in a future that why and how expanded CAG repeat, which translated into poly glutamine chain, causes a selective neuronal cell dearth.