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Journal Articles Brain - A Journal of Neurology Year : 2019

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

Michael Flower (1) , Vilija Lomeikaite (2) , Marc Ciosi (2) , Sarah Cumming (2) , Fernando Morales (2, 3) , Kitty Lo (4) , Davina Hensman Moss (1) , Lesley Jones (5) , Peter Holmans (5) , Darren G Monckton , Sarah J Tabrizi (1) , Peter Kraus , Rainer Hoffman , Alan Tobin , Beth Borowsky , S Keenan , Kathryn B Whitlock , Sarah Queller , Colin Campbell , Chiachi Wang , Doug Langbehn , Eric Axelson , Hans Johnson , Tanka Acharya , Dave M Cash , Chris Frost , Rebecca Jones , Caroline Jurgens , Jeroen van der Grond , Marie-Noelle N Witjes- Ane , Raymund a C Roos , Eve M Dumas , Simon J A van den Bogaard , Cheryl Stopford , David Craufurd , Jenny Callaghan , Natalie Arran , Diana D Rosas , S Lee , W Monaco , Alison O’regan , Cassie Milchman , E Frajman , Izelle Labuschagne , Julie Stout , Melissa Campbell , Sophie C Andrews , Natalie Bechtel , Ralf Reilmann , Stefan Bohlen , Chris Kennard , Claire Berna , Stephen Hicks , Alexandra Durr (6) , C Pourchot , Eric Bardinet (6) , Kevin Nigaud , Romain Valabregue (6) , Stephane Lehericy (6) , Cecilia Marelli , Celine Jauffret , Damian Justo , Blair Leavitt , Joji Decolongon , Aaron Sturrock , Alison Coleman , Rachelle Dar Santos , A Patel , Claire Gibbard , Daisy Whitehead , Ed Wild , Gail Owen , Helen Crawford , Ian Malone , Nayana Lahiri , Nick C Fox , Nicola Z Hobbs , Rachael I Scahill , Roger Ordidge , Tracey Pepple , Joy Read , Miranda J Say , Bernhard Landwehrmeyer , Ferroudja Daidj , Guillaume Bassez , Baptiste Lignier , Florence Couppey , Stéphanie Delmas , Jean-François Deux , Karolina Hankiewicz , Celine Dogan , Lisa Minier , Pascale Chevalier , Amira Hamadouche , Michael Catt , Vincent van Hees , Sharon Catt , Ameli Schwalber , Juliane Dittrich , Marie Kierkegaard , Stephan Wenninger , Benedikt Schoser , Angela Schüller , Kristina Stahl , Heike Künzel , Martin Wolff , Anna Jellinek , Cecilia Jimenez Moreno , Grainne Gorman , Hanns Lochmüller , Michael Trenell , Sandra van Laar , Libby Wood , Sophie Cassidy , Jane Newman , Sarah Charman , Renae Steffaneti , Louise Taylor , Allan Brownrigg , Sharon Day , Antonio Atalaia , Joost Raaphorst , Kees Okkersen , Baziel van Engelen , Stephanie Nikolaus , Yvonne Cornelissen , Marlies van Nimwegen , Daphne Maas , Ellen Klerks , Sacha Bouman , Hans Knoop , Linda Heskamp , Arend Heerschap , Ridho Rahmadi , Perry Groot , Tom Heskes , Katarzyna Kapusta , Jeffrey Glennon , Shaghayegh Abghari , Armaz Aschrafi , Geert Poelmans , Shaun Treweek , Fiona Hogarth , Roberta Littleford , Peter Donnan , Adrian Hapca , Michael Hannah , Emma Mckenzie , Petra Rauchhaus , Sarah Cumming , Darren G Monckton , Berit Adam , Catharina Faber , Ingemar Merkies
Lesley Jones
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Peter Holmans
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Darren G Monckton
  • Function : Author
Sarah J Tabrizi
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Peter Kraus
  • Function : Author
Rainer Hoffman
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Alan Tobin
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Beth Borowsky
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S Keenan
  • Function : Author
Kathryn B Whitlock
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Sarah Queller
  • Function : Author
Colin Campbell
  • Function : Author
Chiachi Wang
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Doug Langbehn
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Eric Axelson
  • Function : Author
Hans Johnson
  • Function : Author
Tanka Acharya
  • Function : Author
Dave M Cash
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Chris Frost
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Rebecca Jones
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Caroline Jurgens
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Jeroen van der Grond
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Marie-Noelle N Witjes- Ane
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Raymund a C Roos
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Eve M Dumas
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Simon J A van den Bogaard
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Cheryl Stopford
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David Craufurd
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Jenny Callaghan
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Natalie Arran
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Diana D Rosas
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S Lee
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W Monaco
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Alison O’regan
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Cassie Milchman
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E Frajman
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Izelle Labuschagne
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Julie Stout
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Melissa Campbell
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Sophie C Andrews
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Natalie Bechtel
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Ralf Reilmann
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Stefan Bohlen
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Chris Kennard
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Claire Berna
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Stephen Hicks
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C Pourchot
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Kevin Nigaud
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Cecilia Marelli
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Celine Jauffret
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Damian Justo
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Blair Leavitt
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Joji Decolongon
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Aaron Sturrock
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Alison Coleman
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Rachelle Dar Santos
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A Patel
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Claire Gibbard
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Daisy Whitehead
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Ed Wild
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Gail Owen
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Helen Crawford
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Ian Malone
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Nayana Lahiri
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Nick C Fox
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Nicola Z Hobbs
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Rachael I Scahill
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Roger Ordidge
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Tracey Pepple
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Joy Read
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Miranda J Say
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Bernhard Landwehrmeyer
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Ferroudja Daidj
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Guillaume Bassez
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Baptiste Lignier
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Florence Couppey
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Stéphanie Delmas
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Jean-François Deux
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Karolina Hankiewicz
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Celine Dogan
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Lisa Minier
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Pascale Chevalier
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Amira Hamadouche
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Michael Catt
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Vincent van Hees
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Sharon Catt
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Ameli Schwalber
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Juliane Dittrich
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Marie Kierkegaard
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Stephan Wenninger
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Benedikt Schoser
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Angela Schüller
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Kristina Stahl
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Heike Künzel
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Martin Wolff
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Anna Jellinek
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Cecilia Jimenez Moreno
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Grainne Gorman
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Hanns Lochmüller
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Michael Trenell
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Sandra van Laar
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Libby Wood
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Sophie Cassidy
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Jane Newman
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Sarah Charman
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Renae Steffaneti
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Louise Taylor
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Allan Brownrigg
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Sharon Day
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Antonio Atalaia
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Joost Raaphorst
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Kees Okkersen
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Baziel van Engelen
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Stephanie Nikolaus
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Yvonne Cornelissen
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Marlies van Nimwegen
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Daphne Maas
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Ellen Klerks
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Sacha Bouman
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Hans Knoop
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Linda Heskamp
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Arend Heerschap
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Ridho Rahmadi
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Perry Groot
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Tom Heskes
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Katarzyna Kapusta
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Jeffrey Glennon
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Shaghayegh Abghari
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Armaz Aschrafi
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Geert Poelmans
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Shaun Treweek
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Fiona Hogarth
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Roberta Littleford
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Peter Donnan
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Adrian Hapca
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Michael Hannah
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Emma Mckenzie
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Petra Rauchhaus
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Sarah Cumming
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Darren G Monckton
Berit Adam
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Catharina Faber
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Ingemar Merkies
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Abstract

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.
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hal-04434732 , version 1 (02-02-2024)

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Michael Flower, Vilija Lomeikaite, Marc Ciosi, Sarah Cumming, Fernando Morales, et al.. MSH3 modifies somatic instability and disease severity in Huntington’s and myotonic dystrophy type 1. Brain - A Journal of Neurology , 2019, 142 (7), pp.1876-1886. ⟨10.1093/brain/awz115⟩. ⟨hal-04434732⟩
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