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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 language | English |
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Pages (from-to) | 1876-1886 |
Number of pages | 11 |
Journal | Brain |
Volume | 142 |
Issue number | 7 |
Early online date | 19 Jun 2019 |
DOIs | |
Publication status | Published - Jul 2019 |
Keywords
- association study
- Huntington's disease
- movement disorders
- myotonic dystrophy
- transcriptomics
ASJC Scopus subject areas
- General Medicine
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Dive into the research topics of 'MSH3 modifies somatic instability and disease severity in Huntington's and myotonic dystrophy type 1'. Together they form a unique fingerprint.Projects
- 1 Finished
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OPTIMISTIC: Observational Prolonged Trial in Myotonic Dystrophy Type 1 to Improve QoL-Standards, a Target Identification Collaboration (joint with Concentris Research Management GmbH,Radboud University Nijmegen-Holland, Newcastle University, Munich University, University of Paris Est Creteil, Glasgow University and Industrial Partner)
Donnan, P. (Investigator)
COMMISSION OF THE EUROPEAN COMMUNITIES
1/11/12 → 30/04/17
Project: Research