TY - JOUR
T1 - MSH3 modifies somatic instability and disease severity in Huntington's and myotonic dystrophy type 1
AU - TRACK-HD investigators
AU - Flower, Michael
AU - Lomeikaite, Vilija
AU - Ciosi, Marc
AU - Cumming, Sarah
AU - Morales, Fernando
AU - Lo, Kitty
AU - Hensman Moss, Davina
AU - Jones, Lesley
AU - Holmans, Peter
AU - Monckton, Darren G.
AU - Tabrizi, Sarah J.
AU - Kraus, Peter
AU - OPTIMISTIC consortium
AU - Hoffman, Rainer
AU - Tobin, Alan
AU - Borowsky, Beth
AU - Keenan, S.
AU - Whitlock, Kathryn B.
AU - Queller, Sarah
AU - Campbell, Colin
AU - Wang, Chiachi
AU - Langbehn, Doug
AU - Axelson, Eric
AU - Johnson, Hans
AU - Acharya, Tanka
AU - Cash, Dave M.
AU - Frost, Chris
AU - Jones, Rebecca
AU - Jurgens, Caroline
AU - Hart, Ellen P. T.
AU - van der Grond, Jeroen
AU - Witjes- Ane, Marie-Noelle N.
AU - Roos, Raymund A. C.
AU - Dumas, Eve M.
AU - van den Bogaard, Simon J. A.
AU - Stopford, Cheryl
AU - Craufurd, David
AU - Callaghan, Jenny
AU - Arran, Natalie
AU - Rosas, Diana D.
AU - Lee, S.
AU - Monaco, W.
AU - O'Regan, Alison
AU - Milchman, Cassie
AU - Frajman, E.
AU - Labuschagne, Izelle
AU - Stout, Julie
AU - Campbell, Melissa
AU - Andrews, Sophie C.
AU - Raaphorst, Joost
AU - Knoop, Hans
PY - 2019/7/1
Y1 - 2019/7/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85072279766&partnerID=8YFLogxK
U2 - https://doi.org/10.1093/brain/awz115
DO - https://doi.org/10.1093/brain/awz115
M3 - Article
C2 - 31216018
SN - 0006-8950
VL - 142
SP - 1876
EP - 1886
JO - Brain
JF - Brain
IS - 7
ER -