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

• Published in: Brain (London, England : 1878) Vol. 142; no. 7; pp. 1876 - 1886
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.07.2019
• Subjects: Human health and pathology; Life Sciences; myotonic dystrophy; transcriptomics; Huntington’s disease; movement disorders; association study; Huntington's disease myotonic dystrophy transcriptomics movement disorders association study; Huntington's disease
• ISSN: 0006-8950; 1460-2156
• DOI: 10.1093/brain/awz115

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.