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Dynamic mutations in genome, like triplet repeat expansion

基因组中的动态突变，例如三联体重复扩增

基本信息

批准号：
07458253
负责人：
YAMADA Masao
金额：
$ 1.41万
依托单位：
National Children's Medical Research Center
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1996
项目状态：
已结题

项目摘要

The remarkable expansion of short stretches of trinucleotide repeats associated with serious neurodegenerative disorders, including Huntington's disease (HD), has emerged as one of the most fascinating phenomena in human genetics. Dentatorubral-pallidoluysian atrophy (DRPLA), almost unheard of in Western countries but a little more common in Japan, has been identified by our group as the seventh member of diseases caused by triplet repeat expansion. To define the molecular basis for the geographic variation in prevalence, we have analyzed haplotypes around the DRPLA repeats in several different ethnic groups. Two intragenic biallelic polymorphisms distinguished three haplotypes, each of which formed a predominant haplotype found in the three major racial populations. All the expanded repeats of Japanese and Caucasian DRPLA patients studied shared a particular haplotype, which otherwise was associated with longer repeats commonly found in Asians. These results support a multi-step model for repeat expansion and suggest that expanded DRPLA repeats may have evolved from an ancient chromosomal haplotype of Asian origin. Chromosomes of the HRS patients, however, were associated with a different haplotype from those in Japanese and Caucasian DRPLA patients. This indicates that a second predisposing haplotype is present in the African population. We also conducted studies for reveal molecular mechanism of neuron death by CAG repeat expansion.

与严重的神经退行性疾病相关的三核苷酸重复短片段的显著扩增，包括亨廷顿病（HD），已经成为人类遗传学中最迷人的现象之一。齿状核红核苍白球路易氏体萎缩症（DRPLA），在西方国家几乎闻所未闻，但在日本更常见，已被我们的小组确定为三联体重复扩增引起的疾病的第七个成员。为了确定患病率地理变异的分子基础，我们分析了几个不同种族群体中DRPLA重复序列周围的单倍型。两个基因内的双等位基因多态性区分三个单倍型，其中每一个形成了一个主要的单倍型中发现的三个主要的种族人群。所有研究的日本和高加索DRPLA患者的扩展重复序列都有一个特定的单倍型，否则与亚洲人常见的较长重复序列相关。这些结果支持重复扩增的多步骤模型，并表明扩展的DRPLA重复序列可能是从亚洲起源的古老染色体单倍型进化而来的。然而，HRS患者的染色体与日本和高加索DRPLA患者的不同单倍型相关。这表明非洲人群中存在第二种易感单倍型。我们还对CAG重复序列扩增导致神经元死亡的分子机制进行了研究。