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MSH3 modifies somatic instability and disease severity in Huntington’s and myotonic dystrophy type 1

Flowers, Michael, Lomeilkaite, Vilila, Ciosi, Marc, Morales, Fernando, Lo, Kitty, Hensman Moss, Davina, Jones, Lesley, Holmans, Peter, Monckton, Darren and Tabrizi, Sarah 2019. MSH3 modifies somatic instability and disease severity in Huntington’s and myotonic dystrophy type 1. Brain 142 (7) , pp. 1876-1886. 10.1093/brain/awz115

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Abstract

The mismatch repair gene MSH3 has been implicated as a genetic modifier of the CAG·CTG repeat expansion disorders Huntington’s disease and myotonic dystrophy type 1. A recent Huntington’s disease genome-wide association study found rs557874766, an imputed single nucleotide polymorphism located within a polymorphic 9 bp tandem repeat in MSH3/DHFR, as the variant most significantly associated with progression in Huntington’s disease. Using Illumina sequencing in Huntington’s disease and myotonic dystrophy type 1 subjects, we show that rs557874766 is an alignment artefact, the minor allele for which corresponds to a three-repeat allele in MSH3 exon 1 that is associated with a reduced rate of somatic CAG·CTG expansion (P = 0.004) and delayed disease onset (P = 0.003) in both Huntington’s disease and myotonic dystrophy type 1, and slower progression (P = 3.86 × 10−7) in Huntington’s disease. RNA-Seq of whole blood in the Huntington’s disease subjects found that repeat variants are associated with MSH3 and DHFR expression. A transcriptome-wide association study in the Huntington’s disease cohort found increased MSH3 and DHFR expression are associated with disease progression. These results suggest that variation in the MSH3 exon 1 repeat region influences somatic expansion and disease phenotype in Huntington’s disease and myotonic dystrophy type 1, and suggests a common DNA repair mechanism operates in both repeat expansion diseases.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher: Oxford University Press
ISSN: 0006-8950
Date of First Compliant Deposit: 12 June 2019
Date of Acceptance: 27 February 2019
Last Modified: 08 Jul 2019 08:21
URI: http://orca-mwe.cf.ac.uk/id/eprint/123201

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