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

Flower, M; Lomeikaite, V; Ciosi, M; Cumming, S; Morales, F; Lo, K; Hensman Moss, D; Jones, L; Holmans, P; TRACK-HD Investigators, ; et al. Flower, M; Lomeikaite, V; Ciosi, M; Cumming, S; Morales, F; Lo, K; Hensman Moss, D; Jones, L; Holmans, P; TRACK-HD Investigators; OPTIMISTIC Consortium; Monckton, DG; Tabrizi, SJ (2019) MSH3 modifies somatic instability and disease severity in Huntington's and myotonic dystrophy type 1. Brain, 142 (7). pp. 1876-1886. ISSN 1460-2156 https://doi.org/10.1093/brain/awz115
SGUL Authors: Lahiri, Nayana Hensman Moss, Davina Jane

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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.

Item Type: Article
Additional Information: © The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: Huntington’s disease, association study, movement disorders, myotonic dystrophy, transcriptomics, TRACK-HD Investigators, OPTIMISTIC Consortium, Huntington's disease, myotonic dystrophy, transcriptomics, movement disorders, association study, 11 Medical and Health Sciences, 17 Psychology and Cognitive Sciences, Neurology & Neurosurgery
SGUL Research Institute / Research Centre: Academic Structure > Institute of Medical & Biomedical Education (IMBE)
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: Brain
ISSN: 1460-2156
Language: eng
Dates:
DateEvent
July 2019Published
19 June 2019Published Online
27 February 2019Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
200181/Z/15/ZWellcome TrustUNSPECIFIED
MR/L010305/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
2012–305121Seventh Framework Programmehttp://dx.doi.org/10.13039/501100004963
305121Seventh Framework Programmehttp://dx.doi.org/10.13039/501100004963
305697Seventh Framework Programmehttp://dx.doi.org/10.13039/501100004963
1477284Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
JS16/M574Rosetrees Trusthttp://dx.doi.org/10.13039/501100000833
200526–01College of Medical, Veterinary and Life Sciences of the University of GlasgowUNSPECIFIED
PubMed ID: 31216018
Web of Science ID: WOS:000481420100015
Go to PubMed abstract
URI: https://openaccess.sgul.ac.uk/id/eprint/113056
Publisher's version: https://doi.org/10.1093/brain/awz115

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