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

Michael Flower, Vilija Lomeikaite, Marc Ciosi, Sarah Cumming, Fernando Morales, Kitty Lo, Davina Hensman Moss, Lesley Jones, Peter Holmans, TRACK-HD Investigators, OPTIMISTIC Consortium, Darren G. Monckton, Sarah J. Tabrizi

Research output: Contribution to journalArticleResearchpeer-review

28 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1876-1886
Number of pages11
Issue number7
Publication statusPublished - Jul 2019


  • association study
  • Huntington's disease
  • movement disorders
  • myotonic dystrophy
  • transcriptomics

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