Gonitel Roman, Moffitt Hilary, Sathasivam Kirupa, Woodman Ben, Detloff Peter J, Faull Richard L M, Bates Gillian P
Department of Medical and Molecular Genetics, King's College London School of Medicine, London SE1 9RT, United Kingdom.
Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3467-72. doi: 10.1073/pnas.0800048105. Epub 2008 Feb 25.
Huntington's disease (HD) is caused by a CAG repeat expansion that is unstable upon germ-line transmission and exhibits mosaicism in somatic tissues. We show that region-specific CAG repeat mosaicism profiles are conserved between several mouse models of HD and therefore develop in a predetermined manner. Furthermore, we demonstrate that these synchronous, radical changes in CAG repeat size occur in terminally differentiated neurons. In HD this ongoing mutation of the repeat continuously generates genetically distinct neuronal populations in the adult brain of mouse models and HD patients. The neuronal population of the striatum is particularly distinguished by a high rate of CAG repeat allele instability and expression driving the repeat upwards and would be expected to enhance its toxicity. In both mice and humans, neurons are distinguished from nonneuronal cells by expression of MSH3, which provides a permissive environment for genetic instability independent of pathology. The neuronal mutations described here accumulate to generate genetically discrete populations of cells in the absence of selection. This is in contrast to the traditional view in which genetically discrete cellular populations are generated by the sequence of random variation, selection, and clonal proliferation. We are unaware of any previous demonstration that mutations can occur in terminally differentiated neurons and provide a proof of principle that, dependent on a specific set of conditions, functional DNA polymorphisms can be produced in adult neurons.
亨廷顿舞蹈症（HD）由CAG重复序列扩增引起，该扩增在种系传递时不稳定，并在体细胞组织中表现出嵌合现象。我们发现，HD的几种小鼠模型之间区域特异性CAG重复嵌合图谱是保守的，因此是以预定方式发展的。此外，我们证明这些CAG重复序列大小的同步、剧烈变化发生在终末分化神经元中。在HD中，这种重复序列的持续突变在小鼠模型和HD患者的成年大脑中不断产生基因上不同的神经元群体。纹状体的神经元群体尤其以CAG重复等位基因的高不稳定性和使重复序列向上表达的速率为特征，预计这会增强其毒性。在小鼠和人类中，神经元通过MSH3的表达与非神经元细胞区分开来，MSH3为独立于病理的基因不稳定性提供了一个宽松的环境。这里描述的神经元突变在没有选择的情况下积累，从而产生基因上离散的细胞群体。这与传统观点相反，传统观点认为基因上离散的细胞群体是由随机变异、选择和克隆增殖序列产生的。我们不知道之前有任何关于终末分化神经元中会发生突变的证明，并且提供了一个原理证明，即取决于一组特定条件，成年神经元中可以产生功能性DNA多态性。
