Instability of expanded CAG/CAA repeats in spinocerebellar ataxia type 17
Instability of expanded CAG/CAA repeats in spinocerebellar ataxia type 17
复制标题
DOI：
10.1038/sj.ejhg.5201954
复制
发表时间：
2008-02-01
影响因子：
5.2
通讯作者：
Lin, Xi
中科院分区：
文献类型：
--
作者：
Gao, Rui;Matsuura, Tohru;Lin, Xi
三核苷酸重复序列扩增是导致多种神经系统疾病的动态突变，其不稳定性受多种因素的影响。重复配置似乎特别重要，纯重复被认为比中断的重复更不稳定。但目前仍缺乏直接证据。在这里，我们对脊髓小脑型共济失调17型(SCA17)的研究有力地支持了这一假说。SCA17是一种典型的聚谷氨酰胺病，由TBP(TATA结合蛋白)中CAG重复序列的扩展引起，其独特之处在于，纯扩展的聚谷氨酰胺束由含有长延伸的纯CAG的简单结构或包含CAA中断的复杂结构编码。通过对不同种族背景的SCA17患者的血DNA进行小池聚合酶链式反应(SP-PCR)分析，我们定量地评估了这两种类型的扩展等位基因编码相似长度的聚谷氨酰胺扩展的不稳定性。携带纯CAG重复序列的患者的突变频率是CAA中断患者的2-3倍。有趣的是，纯净的CAG重复序列既有扩增又有缺失，而中断的重复序列以显著较低的频率表现出大部分缺失。这些数据有力地表明，重复结构是不稳定的关键决定因素，CAA中断可能是SCA17基因中CAG重复序列进一步扩大的限制因素，这表明在CAG扩张中断的SCA17家族中缺乏预期的分子基础。
Trinucleotide repeat expansions are dynamic mutations causing many neurological disorders, and their instability is influenced by multiple factors. Repeat configuration seems particularly important, and pure repeats are thought to be more unstable than interrupted repeats. But direct evidence is still lacking. Here, we presented strong support for this hypothesis from our studies on spinocerebellar ataxia type 17 (SCA17). SCA17 is a typical polyglutamine disease caused by CAG repeat expansion in TBP (TATA binding protein), and is unique in that the pure expanded polyglutamine tract is coded by either a simple configuration with long stretches of pure CAGs or a complex configuration containing CAA interruptions. By small pool PCR (SP-PCR) analysis of blood DNA from SCA17 patients of distinct racial backgrounds, we quantitatively assessed the instability of these two types of expanded alleles coding similar length of polyglutamine expansion. Mutation frequency in patients harboring pure CAG repeats is 2-3 folds of those with CAA interruptions. Interestingly, the pure CAG repeats showed both expansion and deletion while the interrupted repeats exhibited mostly deletion at a significantly lower frequency. These data strongly suggest that repeat configuration is a critical determinant for instability, and CAA interruptions might serve as a limiting element for further expansion of CAG repeats in SCA17 locus, suggesting a molecular basis for lack of anticipation in SCA17 families with interrupted CAG expansion.