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

, OPTIMISTIC consortium, Michael Flower, Vilija Lomeikaite, Marc Ciosi, Sarah Cumming, Fernando Morales, Kitty Lo, Davina Hensman Moss, Lesley Jones, Peter Holmans, Darren G. Monckton, Sarah J. Tabrizi, Louise Taylor, Shaun Treweek, Fiona Hogarth, Roberta Littleford, Peter Donnan, Adrian Hapca, Emma MckenziePetra Rauchhaus

Research output: Contribution to journalArticlepeer-review

95 Citations (Scopus)
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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.

Original languageEnglish
Pages (from-to)1876-1886
Number of pages11
JournalBrain
Volume142
Issue number7
Early online date19 Jun 2019
DOIs
Publication statusPublished - Jul 2019

Keywords

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

ASJC Scopus subject areas

  • General Medicine

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