CAG repeat instability at SCA2 locus: anchoring CAA interruptions and linked single nucleotide polymorphisms
CAG repeat instability at SCA2 locus: anchoring CAA interruptions and linked single nucleotide polymorphisms
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DOI：
10.1093/hmg/10.21.2437
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发表时间：
2001-10-02
影响因子：
3.5
通讯作者：
Brahmachari, SK
中科院分区：
文献类型：
--
作者：
Choudhry, S;Mukerji, M;Brahmachari, SK
脊髓小脑性共济失调2（SCA2）是一种常染色体显性遗传性神经退行性疾病，由SCA2基因外显子1内的隐蔽CAG重复序列扩增引起。正常个体的CAG重复序列长度从14到31个不等，并且经常被一个或多个CAA三联体中断，而扩展的等位基因包含34到59个CAG重复序列的纯不间断延伸。我们以前曾报道，在印度人口中存在一个有限的池的“祖先”或“在风险”的扩展SCA2等位基因的单倍型。我们现在报告的两个新的单核苷酸多态性（SNPs）的SCA2基因的外显子1和他们的特点，在215个正常和64个扩展染色体的鉴定。两个双等位基因SNP区分两个单倍型，GT和CC，其中每一个形成了一个主要的单倍型与正常和扩展SCA2等位基因。所有扩增的等位基因均以CC单倍型分离，而CC单倍型仅与29.3%的正常染色体相关。CAA散布分析显示，大多数具有CC单倍型的正常等位基因是纯的或缺少最近端5' CAA中断。SCA2位点的重复序列长度变化也呈极性，主要发生在重复序列的5'端。我们的研究结果表明，CAA中断在赋予SCA2重复序列的稳定性方面起着重要作用，并且它们的缺失使等位基因倾向于不稳定和病理性扩增。我们的研究还提供了与SCA2相关的新的单倍型，这些单倍型应被证明有助于进一步了解SCA2位点的突变历史和重复不稳定性机制。
Spinocerebellar ataxia 2 (SCA2) is an autosomal dominant neurodegenerative disorder that results from the expansion of a cryptic CAG repeat within the exon 1 of the SCA2 gene. The CAG repeat in normal individuals varies in length from 14 to 31 repeats and is frequently interrupted by one or more CAA triplets, whereas the expanded alleles contain a pure uninterrupted stretch of 34 to 59 CAG repeats. We have previously reported the presence of a limited pool of 'ancestral' or 'at risk' haplotypes for the expanded SCA2 alleles in the Indian population. We now report the identification of two novel single nucleotide polymorphisms (SNPs) in exon 1 of the SCA2 gene and their characterization in 215 normal and 64 expanded chromosomes. The two biallelic SNPs distinguished two haplotypes, GT and CC, each of which formed a predominant haplotype associated with normal and expanded SCA2 alleles. All the expanded alleles segregated with CC haplotype, which otherwise was associated with only 29.3% of the normal chromosomes. CAA interspersion analysis revealed that majority of the normal alleles with CC haplotype were either pure or lacked the most proximal 5' CAA interruption. The repeat length variation at SCA2 locus also appeared to be polar with changes occurring mostly at the 5' end of the repeat. Our results demonstrate that CAA interruptions play an important role in conferring stability to SCA2 repeat and their absence predisposes alleles towards instability and pathological expansion. Our study also provides new haplotypes associated with SCA2 that should prove useful in further understanding the mutational history and mechanism of repeat instability at the SCA2 locus.