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

Fernande Freyermuth, Frédérique Rau, Yosuke Kokunai, Thomas Linke, Chantal Sellier, Masayuki Nakamori, Yoshihiro Kino, Ludovic Arandel, Arnaud Jollet, Christelle Thibault, Muriel Philipps, Serge Vicaire, Bernard Jost, Bjarne Udd, John W. Day, Denis Duboc, Karim Wahbi, Tsuyoshi Matsumura, Harutoshi Fujimura, Hideki Mochizuki, François Deryckere, Takashi Kimura, Nobuyuki Nukina, Shoichi Ishiura, Vincent Lacroix, Amandine Campan-Fournier, Vincent Navratil, Emilie Chautard, Didier Auboeuf, Minoru Horie, Keiji Imoto, Kuang-Yung Lee, Maurice S. Swanson, Adolfo Lopez de Munain, Shin Inada, Hideki Itoh, Kazuo Nakazawa, Takashi Ashihara, Eric Wang, Thomas Zimmer, Denis Furling (), Masanori P. Takahashi () and Nicolas Charlet-Berguerand ()
Additional contact information
Fernande Freyermuth: Department of Translational medicine and neurogenetics
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
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

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11067

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