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

Flower, M. et al. (2019) MSH3 modifies somatic instability and disease severity in Huntington's and myotonic dystrophy type 1. Brain, 142(7), pp. 1876-1886. (doi: 10.1093/brain/awz115) (PMID:31216018) (PMCID:PMC6598626)

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: Articles
• Additional Information: This work was in part supported by the UK Dementia Research Institute, European Union, Medical Research Council (UK), Rosetrees Trust, CHDI, and Myotonic Dystrophy Support Group. We thank the CHDI Foundation, a non-profit biomedical research organization exclusively dedicated to developing therapeutics that will substantially improve the lives of Huntington’s disease affected individuals, who funded the TRACK-HD study; the European Union’s Seventh Framework Programme (FP7/2007–2013) under grant agreement no 2012–305121 “Integrated European –omics research project for diagnosis and therapy in rare neuromuscular and neurodegenerative diseases (NEUROMICS)” [305121] and no 305697 (the OPTIMISTIC project); the Medical Research Council (MRC) for their support of the MRC Centre for Neuropsychiatric Genetics and Genomics, MR/L010305/1, and PhD studentship to MF (1477284); the Rosetrees Trust, a private, family funded charity that supports medical research (JS16/M574); College of Medical, Veterinary and Life Sciences of University of Glasgow for PhD studentship to V.L. (200526–01). This work was supported by the UK Dementia Research Institute which receives its funding from DRI Ltd, funded by the UK Medical Research Council, Alzheimer’s Society and Alzheimer’s Research UK.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Morales Montero, Mr Fernando and Cumming, Dr Sarah and Monckton, Professor Darren and Lomeikaite, Vilija and Ciosi, Dr Marc
• Authors: Flower, M., Lomeikaite, V., Ciosi, M., Cumming, S., Morales, F., Lo, K., Hensman Moss, D., Jones, L., Holmans, P., Monckton, D. G., and Tabrizi, S. J.
• College/School: College of Medical Veterinary and Life Sciences; College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
• Journal Name: Brain
• Publisher: Oxford University Press
• ISSN: 0006-8950
• ISSN (Online): 1460-2156
• Published Online: 19 June 2019
• Copyright Holders: Copyright © 2019 The Authors
• First Published: First published in Brain 142(7):1876-1886
• Publisher Policy: Reproduced under a Creative Commons License