Dramatic tissue-specific mutation length increases are an early molecular event in Huntington disease pathogenesis
Dramatic tissue-specific mutation length increases are an early molecular event in Huntington disease pathogenesis
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DOI：
10.1093/hmg/ddg352
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发表时间：
2003-12-15
影响因子：
3.5
通讯作者：
Shelbourne, PF
中科院分区：
文献类型：
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作者：
Kennedy, L;Evans, E;Shelbourne, PF
亨廷顿病是由编码亨廷顿蛋白中延长的谷氨酰胺链的 CAG 重复序列的扩展引起的。尽管突变蛋白广泛表达，但最早和最显着的神经病理变化是在纹状体中观察到的。在这里，我们展示了人类纹状体细胞在病程早期（很可能是在病理性细胞损失开始之前）突变长度的显着增加（最多增加 1000 个 CAG 重复）。敲入 HD 小鼠模型的研究表明，初始 CAG 重复突变的大小可能会影响年龄依赖性、扩展偏向的突变长度变异的起始和组织特异性模式。鉴于 CAG 重复长度与临床严重程度密切相关，我们认为突变长度的体细胞增加可能在成人发病和青少年发病 HD 发病机制的进展性和细胞选择性方面发挥重要作用，我们讨论了对所提供数据的这种解释的含义。
Huntington disease is caused by the expansion of a CAG repeat encoding an extended glutamine tract in a protein called huntingtin. Although the mutant protein is widely expressed, the earliest and most striking neuropathological changes are observed in the striatum. Here we show dramatic mutation length increases (gains of up to 1000 CAG repeats) in human striatal cells early in the disease course, most likely before the onset of pathological cell loss. Studies of knock-in HD mouse models indicate that the size of the initial CAG repeat mutation may influence both onset and tissue-specific patterns of age-dependent, expansion-biased mutation length variability. Given that CAG repeat length strongly correlates with clinical severity, we suggest that somatic increases of mutation length may play a major role in the progressive nature and cell-selective aspects of both adult-onset and juvenile-onset HD pathogenesis and we discuss the implications of this interpretation of the data presented.