Choudhry S, Mukerji M, Srivastava A K, Jain S, Brahmachari S K
Functional Genomics Unit, Centre for Biochemical Technology (CSIR), Mall Road, Delhi, India.
Hum Mol Genet. 2001 Oct 1;10(21):2437-46. doi: 10.1093/hmg/10.21.2437.
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.
脊髓小脑共济失调2型（SCA2）是一种常染色体显性神经退行性疾病，由SCA2基因第1外显子中一个隐蔽的CAG重复序列扩增所致。正常个体中的CAG重复序列长度在14至31次重复之间变化，并且经常被一个或多个CAA三联体打断，而扩增的等位基因包含34至59次CAG重复的纯不间断序列。我们之前报道过，在印度人群中，扩增的SCA2等位基因存在有限的“祖先”或“风险”单倍型库。我们现在报告在SCA2基因第1外显子中鉴定出两个新的单核苷酸多态性（SNP），并在215条正常染色体和64条扩增染色体中对其进行了特征分析。这两个双等位基因SNP区分出两种单倍型，GT和CC，每种单倍型都形成了与正常和扩增的SCA2等位基因相关的主要单倍型。所有扩增的等位基因都与CC单倍型分离，否则该单倍型仅与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要么是纯合的，要么缺乏最靠近5'端的CAA中断。SCA2位点的重复长度变异似乎也具有极性，变化主要发生在重复序列的5'端。我们的结果表明，CAA中断在赋予SCA2重复序列稳定性方面起着重要作用，而它们的缺失使等位基因易于不稳定和病理性扩增。我们的研究还提供了与SCA2相关的新单倍型，这将有助于进一步了解SCA2位点的突变历史和重复序列不稳定性的机制。
