Kennedy Laura, Evans Elizabeth, Chen Chiung-Mei, Craven Lyndsey, Detloff Peter J, Ennis Margaret, Shelbourne Peggy F
Division of Molecular Genetics, Faculty of Biomedical and Life Scienes, University of Glasgow, Anderson College Complex, 56 Dumbarton Road, Glasgow G11 6NU, UK.
Hum Mol Genet. 2003 Dec 15;12(24):3359-67. doi: 10.1093/hmg/ddg352. Epub 2003 Oct 21.
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.
亨廷顿舞蹈症是由一个CAG重复序列的扩增引起的，该重复序列编码一种名为亨廷顿蛋白的蛋白质中的一段延长的谷氨酰胺序列。尽管突变蛋白广泛表达，但最早且最显著的神经病理学变化出现在纹状体中。在这里，我们展示了在疾病进程早期，人类纹状体细胞中显著的突变长度增加（增加多达1000个CAG重复序列），很可能发生在病理性细胞丢失开始之前。对敲入型亨廷顿舞蹈症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、扩增偏向性突变长度变异性的发病年龄和组织特异性模式。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型和青少年发病型亨廷顿舞蹈症发病机制的进行性本质和细胞选择性方面起主要作用，并且我们讨论了这种对所呈现数据的解释的含义。
