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

Flower, Michael, Lomeilkaite, Vilila, Ciosi, Marc, Cumming, Sarah, Morales, Fernando, Lo, Kitty, Hensman Moss, Davina, Jones, Lesley ORCID: https://orcid.org/0000-0002-3007-4612, Holmans, Peter ORCID: https://orcid.org/0000-0003-0870-9412, Monckton, Darren G., Tabrizi, Sarah J., Kraus, Peter, Hoffman, Rainer, Tobin, Alan, Borowsky, Beth, Keenan, S., Whitlock, Kathryn B., Queller, Sarah, Campbell, Colin, Wang, Chiachi, Langbehn, Doug, Axelson, Eric, Johnson, Hans, Acharya, Tanka, Cash, Dave M., Frost, Chris, Jones, Rebecca ORCID: https://orcid.org/0000-0002-3007-4612, Jurgens, Caroline, ‘t Hart, Ellen P., van der Grond, Jeroen, Witjes- Ane, Marie-Noelle N., Roos, Raymund A. C., Dumas, Eve M., van den Bogaard, Simon J. A., Stopford, Cheryl, Craufurd, David, Callaghan, Jenny, Arran, Natalie, Rosas, Diana D., Lee, S., Monaco, W., O’Regan, Alison, Milchman, Cassie, Frajman, E., Labuschagne, Izelle, Stout, Julie, Campbell, Melissa, Andrews, Sophie C., Bechtel, Natalie, Reilmann, Ralf, Bohlen, Stefan, Kennard, Chris, Berna, Claire, Hicks, Stephen, Durr, Alexandra, Pourchot, C., Bardinet, Eric, Nigaud, Kevin, Valabre`gue, Romain, Lehericy, Stephane, Marelli, Cecilia, Jauffret, Celine, Justo, Damian, Leavitt, Blair, Decolongon, Joji, Sturrock, Aaron, Coleman, Alison, Dar Santos, Rachelle, Patel, A., Gibbard, Claire, Whitehead, Daisy, Wild, Ed, Owen, Gail, Crawford, Helen, Malone, Ian, Lahiri, Nayana, Fox, Nick C., Hobbs, Nicola Z., Scahill, Rachael I., Ordidge, Roger, Pepple, Tracey, Read, Joy, Say, Miranda J., Landwehrmeyer, Bernhard, Daidj, Ferroudja, Bassez, Guillaume, Lignier, Baptiste, Couppey, Florence, Delmas, Stéphanie, Deux, Jean-François, Hankiewicz, Karolina, Dogan, Celine, Minier, Lisa, Chevalier, Pascale, Hamadouche, Amira, Catt, Michael, van Hees, Vincent, Catt, Sharon, Schwalber, Ameli, Dittrich, Juliane, Kierkegaard, Marie, Wenninger, Stephan, Schoser, Benedikt, Schüller, Angela, Stahl, Kristina, Künzel, Heike, Wolff, Martin, Jellinek, Anna, Moreno, Cecilia Jimenez, Gorman, Grainne, Lochmüller, Hanns, Trenell, Michael, van Laar, Sandra, Wood, Libby, Cassidy, Sophie, Newman, Jane, Charman, Sarah, Steffaneti, Renae, Taylor, Louise, Brownrigg, Allan, Day, Sharon, Atalaia, Antonio, Raaphorst, Joost, Okkersen, Kees, Engelen, Baziel van, Nikolaus, Stephanie, Cornelissen, Yvonne, van Nimwegen, Marlies, Maas, Daphne, Klerks, Ellen, Bouman, Sacha, Knoop, Hans, Heskamp, Linda, Heerschap, Arend, Rahmadi, Ridho, Groot, Perry, Heskes, Tom, Kapusta, Katarzyna, Glennon, Jeffrey, Abghari, Shaghayegh, Aschrafi, Armaz, Poelmans, Geert, Treweek, Shaun, Hogarth, Fiona, Littleford, Roberta, Donnan, Peter, Hapca, Adrian, Hannah, Michael, McKenzie, Emma, Rauchhaus, Petra, Cumming, Sarah A., Adam, Berit, Faber, Catharina, Merkies, Ingemar, TRACK-HD Investigators and OPTIMISTIC Consortium 2019. MSH3 modifies somatic instability and disease severity in Huntington’s and myotonic dystrophy type 1. Brain 142 (7) , pp. 1876-1886. 10.1093/brain/awz115

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Additional Information:	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 cited.
Publisher:	Oxford University Press
ISSN:	0006-8950
Date of First Compliant Deposit:	12 June 2019
Date of Acceptance:	27 February 2019
Last Modified:	03 May 2023 04:36
URI:	https://orca.cardiff.ac.uk/id/eprint/123201

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