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A Complete Association of an intronic SNP rs6798742 with Origin of Spinocerebellar Ataxia Type 7-CAG Expansion Loci in the Indian and Mexican Population.

Authors
  • Faruq, Mohammed1
  • Magaña, Jonathan J2
  • Suroliya, Varun3
  • Narang, Ankita1
  • Murillo-Melo, Nadia M2
  • Hernández-Hernández, Oscar2
  • Srivastava, Achal K3
  • Mukerji, Mitali1
  • 1 Genomics and Molecular Medicine, Council of Scientific and Industrial Research-Institute of Genomics and Integrative Biology (CSIR -IGIB), Mall Road, Delhi, India. , (India)
  • 2 Laboratory of Genomic Medicine, Department of Genetics, National Rehabilitation Institute-LGII (INR-LGII), Mexico City, Mexico. , (Mexico)
  • 3 Department of Neurology, Neuroscience Centre, All India Institute of Medical Sciences, New Delhi, India. , (India)
Type
Published Article
Journal
Annals of Human Genetics
Publisher
Wiley (Blackwell Publishing)
Publication Date
Sep 01, 2017
Volume
81
Issue
5
Pages
197–204
Identifiers
DOI: 10.1111/ahg.12200
PMID: 28597910
Source
Medline
Keywords
License
Unknown

Abstract

Spinocerebellar ataxia type 7 (SCA7) is a rare neurogenetic disorder caused by highly unstable CAG repeat expansion mutation in coding region of SCA7. We aimed to understand the effect of diverse ATXN7 cis-element in correlation with CAG expansion mutation of SCA7. We initially performed an analysis to identify the haplotype background of CAG expanded alleles using eight bi-allelic single nucleotide polymorphisms (SNPs) flanking an ATXN7-CAG expansion in 32 individuals from nine unrelated Indian SCA7 families and 88 healthy controls. Subsequent validation of the findings was performed in 89 ATXN7-CAG mutation carriers and in 119 unrelated healthy controls of Mexican ancestry. The haplotype analyses showed a shared haplotype background and C allele of SNP rs6798742 (approximately 6 kb from the 3'-end of CAG repeats) is in complete association with expanded, premutation, intermediate, and the majority of large normal (≥12) CAG allele. The C allele (ancestral/chimp allele) association was validated in SCA7 subjects and healthy controls from Mexico, suggesting its substantial association with CAG expanded and expansion-prone chromosomes. Analysis of rs6798742 and other neighboring functional SNPs within 6 kb in experimental datasets (Encyclopedia of DNA Elements; ENCODE) shows functional marks that could affect transcription as well as histone methylation. An allelic association of the CAG region to an intronic SNP in two different ethnic and geographical populations suggests a -cis factor-dependent mechanism in ATXN7 CAG-region expansion.

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