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

• Published in: Brain (London, England : 1878) Vol. 142; no. 7; pp. 1876 - 1886
• Main Authors: 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, ‘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, Romain, gue, `, 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
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.07.2019
• Subjects: Human health and pathology; Life Sciences; myotonic dystrophy; transcriptomics; Huntington’s disease; movement disorders; association study; Huntington's disease myotonic dystrophy transcriptomics movement disorders association study; Huntington's disease
• ISSN: 0006-8950; 1460-2156; 1460-2156
• DOI: 10.1093/brain/awz115

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.