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Flower, Michael; Lomeikaite, Vilija; Ciosi, Marc; Cumming, Sarah; Morales, Fernando; Lo, Kitty; Hensman Moss, Davina; Jones, Lesley; Holmans, Peter; Monckton, Darren G; Tabrizi, Sarah J; Kraus, Peter; Hoffman, Rainer; Tobin, Alan; Borowsky, Beth; Keenan, S; Whitlock, Kathryn B; Queller, Sarah; Campbell, Colin; Wang, Chiachi; Langbehn, Doug; Axelson, Eric; Johnson, Hans; Acharya, Tanka; [...]

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

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  • Media type: E-Article
  • Title: MSH3 modifies somatic instability and disease severity in Huntington’s and myotonic dystrophy type 1
  • Contributor: Flower, Michael; Lomeikaite, Vilija; Ciosi, Marc; Cumming, Sarah; Morales, Fernando; Lo, Kitty; Hensman Moss, Davina; Jones, Lesley; Holmans, Peter; Monckton, Darren G; Tabrizi, Sarah J; Kraus, Peter; Hoffman, Rainer; Tobin, Alan; Borowsky, Beth; Keenan, S; Whitlock, Kathryn B; Queller, Sarah; Campbell, Colin; Wang, Chiachi; Langbehn, Doug; Axelson, Eric; Johnson, Hans; Acharya, Tanka; [...]
  • Published: Oxford University Press (OUP), 2019
  • Published in: Brain, 142 (2019) 7, Seite 1876-1886
  • Language: English
  • DOI: 10.1093/brain/awz115
  • ISSN: 0006-8950; 1460-2156
  • Origination:
  • Footnote:
  • Description: <jats:title>Abstract</jats:title> <jats:p>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.</jats:p>
  • Access State: Open Access