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

Autor:	Flower M; Department of Neurodegenerative Disease and Dementia Research Institute, UCL, UK., Lomeikaite V; Institute of Molecular, Cell and Systems Biology, University of Glasgow, UK., Ciosi M; Institute of Molecular, Cell and Systems Biology, University of Glasgow, UK., Cumming S; Institute of Molecular, Cell and Systems Biology, University of Glasgow, UK., Morales F; 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., Lo K; School of Mathematics and Statistics, University of Sydney, Australia., Hensman Moss D; Department of Neurodegenerative Disease and Dementia Research Institute, UCL, UK., Jones L; MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, UK., Holmans P; MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, UK., Monckton DG; Institute of Molecular, Cell and Systems Biology, University of Glasgow, UK., Tabrizi SJ; Department of Neurodegenerative Disease and Dementia Research Institute, UCL, UK.
Jazyk:	angličtina
Zdroj:	Brain : a journal of neurology [Brain] 2019 Jun 19. Date of Electronic Publication: 2019 Jun 19.
DOI:	10.1093/brain/awz115
Abstrakt:	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. (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain.)
Databáze:	MEDLINE
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