MSH3 modifies somatic instability and disease severity in Huntington’s and myotonic dystrophy type 1
Archive ouverte
Flower, Michael | Lomeikaite, Vilija | Ciosi, Marc | Cumming, Sarah | Morales, Fernando | Lo, Kitty | Hensman Moss, Davina | Jones, Lesley | Holmans, Peter | 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 | Jurgens, Caroline | 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 | Valabregue, Romain | Lehericy, Stephane | Marelli, Cecilia | Jauffret, Celine | Justo, Damian | Leavitt, Blair | Decolongon, Joji | Sturrock, Aaron | Coleman, Alison | Santos, Rachelle Dar | 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 | van Engelen, Baziel | 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 | Adam, Berit | Faber, Catharina | Merkies, Ingemar
Edité par
CCSD ; Oxford University Press -
International audience.
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.
