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

Artículo científico
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Fernando Morales.pdf (883.1Kb)
Date
2019-07
Author
Flower, Michael
Lomeikaite, Vilija
Ciosi, Marc
Cumming, Sarah
Morales Montero, Fernando
Lo, Kitty
Hensman Moss, Davina
Jones, Lesley
Holmans, Peter A.
TRACK-HD Investigators
OPTIMISTIC Consortium
Monckton, Darren G.
Tabrizi, Sarah J.
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Abstract
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.
URI
http://hdl.handle.net/10669/80324
External link to the item
https://doi.org/10.1093/brain/awz115
https://academic.oup.com/brain/article/142/7/1876/5520687
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  • Repositorios universitarios

  • Repositorio del SIBDI-UCR
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  • Biblioteca Digital Carlos Melendez (CIHAC)
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  • Directory of Open Access Journals (DOAJ)
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Contact Us | Send Feedback
Repositorio Institucional de la Universidad de Costa Rica. Algunos derechos reservados. Este repositorio funciona con DSpace.
Universidad de Costa Rica