| Research Abstract |
Huntington's disease is an autosomal dominant neurodegenerative disorder. Its causal gene was located at the short arm of chromosome 4.Immediately before the start of this project, the gene for Huntington'd siease was identified by Gusella in Boston. Therefore, in the middle of the term, the aims of this study was shifted to the molecular biological analysis of the CAG repeat of the gene.
(1) In order to identify the causal gene for Huntington's disease, we constructed the yeast artificial chromosome (YAC) and using this several hitherto unknown genes were cloned from the Huntington's disease region. However, those are not related to Huntington's disease, unfortunately.
(2) After the identification of IT15 gene as the gene for Huntington's disease, CAG repeat number was extensively investigated. The distribution of the number of CAG repeat in Japanese normal people and Huntington's disease patient were exactly the same as those of the Western countries. When the CAG repeat number of Hunt
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ington's disease patients were plotted against the age at onset, there was clear inverse correlation ; longer the earlier onset and shorter the later onset. In cases of juvenile onset of the disease ; younger than 20 years old, the gene for the disease comes from the father whose sperms should have various numbers of CAG repeat. Moreover, the frequency of the individual having intermediate number of CAG repeat was obviously high in Western countries in which the frequency of the disease is also high, and vice versa.
(3) There is a polymorphism in the CCG repeat located just after the CAG repeat in IT15 gene. Using this as a marker, we performed an haplotype analysis. We found that the the origin of Japanese Huntington's disease should be not Western countries but somewhere in Asia or Japan.
(4) The CAG repeat is located just in the coding region of IT15 gene. Therefore, the protein having abnormally long glutamine stretch should be expressed in brain. We raised the specific antibody against the IT15 gene product (huntingtin) and performed Western analysis. We found the actual expression of huntingtin in every tissue in the central nervous system. Less
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