CAG repeat instability at SCA2 locus: anchoring CAA interruptions and linked single nucleotide polymorphisms

Choudhry, Shweta and Mukerji, Mitali and Srivastava, Achal K and Jain, Satish and Brahmachari, Samir K (2001) CAG repeat instability at SCA2 locus: anchoring CAA interruptions and linked single nucleotide polymorphisms. In: Human Molecular Genetics, 10 (21). pp. 2437-2446.

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Abstract

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 normalindividuals 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 haracterization 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.

Item Type:	Journal Article
Publication:	Human Molecular Genetics
Publisher:	Oxford University Press
Additional Information:	Copyright of this article belongs to Oxford University Press.
Department/Centre:	Division of Biological Sciences > Molecular Biophysics Unit
Date Deposited:	26 Sep 2008 06:24
Last Modified:	19 Sep 2010 04:50
URI:	http://eprints.iisc.ac.in/id/eprint/16033

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