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Splicing misregulation of SCN5A contributes to cardiac-conduction delay and heart arrhythmia in myotonic dystrophy

Author

Listed:
  • Fernande Freyermuth

    (Department of Translational medicine and neurogenetics
    Present address: Massachusetts General Hospital, MassGeneral Institute for Neurodegenerative Diseases, Charlestown, Massachusetts 02129, USA)

  • Frédérique Rau

    (Sorbonne Universités UPMC Univ Paris 06, Inserm, CNRS, Centre de Recherche en Myologie UMRS974/FRE3617)

  • Yosuke Kokunai

    (Osaka University Graduate School of Medicine)

  • Thomas Linke

    (Friedrich Schiller University Hospital)

  • Chantal Sellier

    (Department of Translational medicine and neurogenetics)

  • Masayuki Nakamori

    (Osaka University Graduate School of Medicine)

  • Yoshihiro Kino

    (Meiji Pharmaceutical University)

  • Ludovic Arandel

    (Sorbonne Universités UPMC Univ Paris 06, Inserm, CNRS, Centre de Recherche en Myologie UMRS974/FRE3617)

  • Arnaud Jollet

    (Sorbonne Universités UPMC Univ Paris 06, Inserm, CNRS, Centre de Recherche en Myologie UMRS974/FRE3617)

  • Christelle Thibault

    (Department of Translational medicine and neurogenetics)

  • Muriel Philipps

    (Department of Translational medicine and neurogenetics)

  • Serge Vicaire

    (Department of Translational medicine and neurogenetics)

  • Bernard Jost

    (Department of Translational medicine and neurogenetics)

  • Bjarne Udd

    (Neuromuscular Research Center, Tampere University and University Hospital
    Folkhälsan Institute of Genetics, Helsinki University
    Vaasa Central Hospital)

  • John W. Day

    (Stanford University)

  • Denis Duboc

    (Service de Cardiologie, Université Paris-Descartes)

  • Karim Wahbi

    (Service de Cardiologie, Université Paris-Descartes)

  • Tsuyoshi Matsumura

    (Toneyama National Hospital)

  • Harutoshi Fujimura

    (Toneyama National Hospital)

  • Hideki Mochizuki

    (Osaka University Graduate School of Medicine)

  • François Deryckere

    (CNRS UMR7175, Ecole Supérieure de Biotechnologies de Strasbourg)

  • Takashi Kimura

    (Hyogo Medical College)

  • Nobuyuki Nukina

    (Laboratory of Structural Neuropathology, Doshisha University Graduate School of Brain Science)

  • Shoichi Ishiura

    (Graduate School of Arts and Sciences, University of Tokyo)

  • Vincent Lacroix

    (Université Lyon 1, CNRS, UMR5558 LBBE)

  • Amandine Campan-Fournier

    (Hospices civils de Lyon, Laboratoire de cytogénétique constitutionelle)

  • Vincent Navratil

    (Pôle Rhône Alpes de Bioinformatique)

  • Emilie Chautard

    (Centre de Recherche en Cancérologie de Lyon)

  • Didier Auboeuf

    (Centre de Recherche en Cancérologie de Lyon)

  • Minoru Horie

    (Shiga Medical University)

  • Keiji Imoto

    (National Institute for Physiological Sciences)

  • Kuang-Yung Lee

    (Chang Gung Memorial Hospital)

  • Maurice S. Swanson

    (Center for NeuroGenetics and the Genetics Institute, University of Florida, College of Medicine)

  • Adolfo Lopez de Munain

    (Hospital Universitario DONOSTIA, Neuroscience Area, Institute Biodonostia CIBERNED and University of Basque Country UPV-EHU)

  • Shin Inada

    (Laboratory of Biomedical Sciences and Information Management, National Cerebral and Cardiovascular Center Research Institute)

  • Hideki Itoh

    (Shiga Medical University)

  • Kazuo Nakazawa

    (Laboratory of Biomedical Sciences and Information Management, National Cerebral and Cardiovascular Center Research Institute)

  • Takashi Ashihara

    (Shiga Medical University)

  • Eric Wang

    (Center for NeuroGenetics and the Genetics Institute, University of Florida, College of Medicine)

  • Thomas Zimmer

    (Friedrich Schiller University Hospital)

  • Denis Furling

    (Sorbonne Universités UPMC Univ Paris 06, Inserm, CNRS, Centre de Recherche en Myologie UMRS974/FRE3617)

  • Masanori P. Takahashi

    (Osaka University Graduate School of Medicine)

  • Nicolas Charlet-Berguerand

    (Department of Translational medicine and neurogenetics)

Abstract

Myotonic dystrophy (DM) is caused by the expression of mutant RNAs containing expanded CUG repeats that sequester muscleblind-like (MBNL) proteins, leading to alternative splicing changes. Cardiac alterations, characterized by conduction delays and arrhythmia, are the second most common cause of death in DM. Using RNA sequencing, here we identify novel splicing alterations in DM heart samples, including a switch from adult exon 6B towards fetal exon 6A in the cardiac sodium channel, SCN5A. We find that MBNL1 regulates alternative splicing of SCN5A mRNA and that the splicing variant of SCN5A produced in DM presents a reduced excitability compared with the control adult isoform. Importantly, reproducing splicing alteration of Scn5a in mice is sufficient to promote heart arrhythmia and cardiac-conduction delay, two predominant features of myotonic dystrophy. In conclusion, misregulation of the alternative splicing of SCN5A may contribute to a subset of the cardiac dysfunctions observed in myotonic dystrophy.

Suggested Citation

  • Fernande Freyermuth & Frédérique Rau & Yosuke Kokunai & Thomas Linke & Chantal Sellier & Masayuki Nakamori & Yoshihiro Kino & Ludovic Arandel & Arnaud Jollet & Christelle Thibault & Muriel Philipps & , 2016. "Splicing misregulation of SCN5A contributes to cardiac-conduction delay and heart arrhythmia in myotonic dystrophy," Nature Communications, Nature, vol. 7(1), pages 1-14, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11067
    DOI: 10.1038/ncomms11067
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    Cited by:

    1. Ryan P. Hildebrandt & Kathryn R. Moss & Aleksandra Janusz-Kaminska & Luke A. Knudson & Lance T. Denes & Tanvi Saxena & Devi Prasad Boggupalli & Zhuangyue Li & Kun Lin & Gary J. Bassell & Eric T. Wang, 2023. "Muscleblind-like proteins use modular domains to localize RNAs by riding kinesins and docking to membranes," Nature Communications, Nature, vol. 14(1), pages 1-19, December.

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