Evolution of the Friedreich's ataxia trinucleotide repeat expansion: Founder effect and premutations
Evolution of the Friedreich's ataxia trinucleotide repeat expansion: Founder effect and premutations
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DOI：
10.1073/pnas.94.14.7452
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发表时间：
1997-07-08
影响因子：
11.1
通讯作者：
Koenig, M
中科院分区：
文献类型：
--
作者：
Cossee, M;Schmitt, M;Koenig, M
弗里德赖希共济失调是最常见的遗传性共济失调，在绝大多数情况下，由共济失调蛋白基因第一内含子中的大GAA重复扩增引起。正常序列对应于具有双峰大小分布的中度多态性三核苷酸重复。小的正常等位基因具有大约8至9个重复，而大的正常等位基因的更异质模式的范围为16至34个GAA。后一类占正常等位基因的约17%。为了确定扩展突变的起源，我们分析了扩展突变或正常等位基因和单倍型的5个多态性标记内或接近共济失调蛋白基因之间的连锁不平衡; 51%的扩展与一个单一的单倍型，和其他扩展与单倍型，可能与主要的一个多态性标记突变或古老的重组。感兴趣的是，与扩增相关的主要单倍型也是与正常大小范围内的较大等位基因相关的主要单倍型，并且几乎从未发现与较小的正常等位基因相关。结果表明，大多数（如果不是所有）大的正常等位基因来自一个单一的创始人染色体，它们代表了一个水库较大的扩展事件，可能通过“前突变”的中间体。事实上，我们发现了两个这样的等位基因（42和60 GAA），经历了灾难性的扩张到病理范围在一个单一的一代。这种逐步进化到大的三核苷酸扩增已经被认为是强直性肌营养不良和脆性X综合征，并可能涉及一个共同的突变机制，尽管序列基序的差异。
Friedreich's ataxia,the most frequent inherited ataxia, is caused, in the vast majority of cases, by large GAA repeat expansions in the first intron of the frataxin gene. The normal sequence corresponds to a moderately polymorphic trinucleotide repeat with bimodal size distribution. Small normal alleles have approximately eight to nine repeats whereas a more heterogeneous mode of large normal alleles ranges from 16 to 34 GAA. The latter class accounts for approximate to 17% of normal alleles. To identify the origin of the expansion mutation, we analyzed linkage disequilibrium between expansion mutations or normal alleles and a haplotype of five polymorphic markers within or close to the frataxin gene; 51% of the expansions were associated with a single haplotype, and the other expansions were associated with haplotypes that could be related to the major one by mutation at a polymorphic marker or by ancient recombination. Of interest, the major haplotype associated with expansion is also the major haplotype associated with the larger alleles in the normal size range and was almost never found associated with the smaller normal alleles. The results indicate that most if not all large normal alleles derive from a single founder chromosome and that they represent a reservoir for larger expansion events, possibly through ''premutation'' intermediates. Indeed, we found two such alleles (42 and 60 GAA) that underwent cataclysmic expansion to pathological range in a single generation. This stepwise evolution to large trinucleotide expansions already was suggested for myotonic dystrophy and fragile X syndrome and may relate to a common mutational mechanism, despite sequence motif differences.