Instability of highly expanded CAG repeats in mice transgenic for the Huntington's disease mutation
Instability of highly expanded CAG repeats in mice transgenic for the Huntington's disease mutation
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DOI：
10.1038/ng0297-197
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发表时间：
1997-02-01
期刊：
影响因子：
30.8
通讯作者：
Bates, GP
中科院分区：
文献类型：
--
作者：
Mangiarini, L;Sathasivam, K;Bates, GP
六种遗传性神经退行性疾病由CAG/聚谷氨酰胺扩增引起，包括脊髓延髓肌萎缩症（SBMA）（1）、亨廷顿病（HD）（2）、脊髓小脑共济失调1型（SCA 1）（3）、齿状核红核苍白球路易体萎缩症（DRPLA）（4，5）、马查多-约瑟夫病（MJD或SCA 3）（6）和SCA 2（7-9）。已经报道了6-39和35-121个重复的正常和扩增的HD等位基因大小（10-13），并且其他疾病的等位基因分布是相当的。代际不稳定性已被描述在所有的情况下，重复往往是更不稳定的父系传递。这可能表现为在HD 14中父系遗传的较大增加，或者表现为在SCA 1中男性传播增加而女性传播减少的趋势（参考文献15）。气孔重复序列的不稳定性在CNS中也是最明显的16，17。主要的例外是小脑，在HD，DRPLA，SCA 1和MJD中，小脑相对于测试的其他大脑区域具有较小的重复（16-21）。在非CNS组织中，在血液、肝脏、肾脏和结肠中观察到不稳定性（16、20、21）。CAG重复序列不稳定性的小鼠模型将有助于解开其分子基础，尽管迄今为止在转基因小鼠中没有CAG重复序列不稳定性的报道。这些研究包括雄激素受体cDNA中的（CAG）（45）（22），HD cDNA中的（CAG）（44）（23），SCA 1 cDNA中的（CAG）（82）（24），SCA 3 cDNA中的（CAG）（79）和分离的（CAC）（79）片段（25）。
Six inherited neurodegenerative diseases are caused by a CAG/polyglutamine expansion, including spinal and bulbar muscular atrophy (SBMA)(1), Huntington's disease (HD)(2), spinocerebellar ataxia type 1 (SCA1)(3), dentatorubral pallidoluysian atrophy (DRPLA)(4,5) Machado-Joseph disease (MJD or SCA3)(6) and SCA2(7-9). Normal and expanded HD allele sizes of 6-39 and 35-121 repeats have been reported(10-13), and the allele distributions for the other diseases are comparable. Intergenerational instability has been described in all cases, and repeats tend to be more unstable on paternal transmission. This may present as larger increases on paternal inheritance as in HD14, or as a tendency to increase on male and decrease on female transmission as in SCA1 (ref.15). Stomatic repeat instability is also appears most pronounced in the CNS16,17. The major exception is the cerebellum, which in HD, DRPLA, SCA1 and MJD has a smaller repeat relative to the other brain regions tested(16-21). Of non-CNS tissues, instability was observed in blood, liver, kidney and colon(16,20,21). A mouse model of CAG repeat instability would be helpful in unravelling its molecular basis although an absence of CAG repeat instability in transgenic mice has so far been reported. These studies include (CAG)(45) in the androgen receptor cDNA(22), (CAG)(44), in the HD cDNA(23), (CAG)(82) in the SCA1 cDNA(24), (CAG)(79) in the SCA3 cDNA and as an isolated (CAC)(79) tract(25).