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MSH3 modifies somatic instability and disease severity in Huntington’s and myotonic dystrophy type 1717.84 kB
Published VersionCC BY V4.0, Open Access
Journal article
MSH3 modifies somatic instability and disease severity in Huntington’s and myotonic dystrophy type 1
Brain, Vol.142(7), pp.1876-1886
2019
PMCID: PMC6598626
PMID: 31216018
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.
Details
- Title
- MSH3 modifies somatic instability and disease severity in Huntington’s and myotonic dystrophy type 1
- Authors
- Michael Flower (Author) - University of GlasgowVilija Lomeikaite (Author) - University of GlasgowMarc Ciosi (Author) - University of GlasgowSarah Cumming (Author) - University of GlasgowFernando Morales (Author) - Universidad de Costa RicaKitty Lo (Author) - The University of SydneyDavina Hensman Moss (Author) - University of GlasgowLesley Jones (Author) - Department of Neurodegenerative Disease and Dementia Research Institute, UCL, UK Institute of Molecular, Cell and Systems Biology, University of Glasgow, UK Instituto de Investigaciones en Salud (INISA), Universidad de Costa Rica, San José, Costa Rica School of Mathematics and Statistics, University of Sydney, Australia MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, UKPeter Holmans (Author) - Cardiff UniversityTRACK-HD Investigators (Author)OPTIMISTIC Consortium (Author)Darren G Monckton (Author) - University of GlasgowSarah J Tabrizi (Corresponding Author) - University of GlasgowSophie Andrews (Consortium Member)
- Publication details
- Brain, Vol.142(7), pp.1876-1886
- Publisher
- Oxford University Press
- Date published
- 2019
- DOI
- 10.1093/brain/awz115
- ISSN
- 1460-2156; 0006-8950
- PMID
- 31216018; PMC6598626
- Copyright note
- 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 cite
- Organisation Unit
- Thompson Institute
- Language
- English
- Record Identifier
- 99659597402621
- Output Type
- Journal article
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