title: Splicing misregulation of SCN5A contributes to cardiac-conduction delay and heart arrhythmia in myotonic dystrophy.
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.
authors.affiliation: Department of Translational medicine and neurogenetics, IGBMC, CNRS UMR7104, INSERM U964, Université de Strasbourg, Illkirch 67400, France.
authors.forename: Fernande
authors.initials: F
authors.lastname: Freyermuth
authors.affiliation: Sorbonne Universités UPMC Univ Paris 06, Inserm, CNRS, Centre de Recherche en Myologie UMRS974/FRE3617, Institut de Myologie, GH Pitié-Salpêtrière, Paris 75013, France.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Rau
authors.affiliation: Department of Neurology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Kokunai
authors.affiliation: Department of Physiology, Friedrich Schiller University Hospital, Jena 07743, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Linke
authors.affiliation: Department of Translational medicine and neurogenetics, IGBMC, CNRS UMR7104, INSERM U964, Université de Strasbourg, Illkirch 67400, France.
authors.forename: Chantal
authors.initials: C
authors.lastname: Sellier
authors.affiliation: Department of Neurology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Nakamori
authors.affiliation: Department of Bioinformatics and Molecular Neuropathology, Meiji Pharmaceutical University, Kiyose 205-8588, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kino
authors.affiliation: Sorbonne Universités UPMC Univ Paris 06, Inserm, CNRS, Centre de Recherche en Myologie UMRS974/FRE3617, Institut de Myologie, GH Pitié-Salpêtrière, Paris 75013, France.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Arandel
authors.affiliation: Sorbonne Universités UPMC Univ Paris 06, Inserm, CNRS, Centre de Recherche en Myologie UMRS974/FRE3617, Institut de Myologie, GH Pitié-Salpêtrière, Paris 75013, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Jollet
authors.affiliation: Department of Translational medicine and neurogenetics, IGBMC, CNRS UMR7104, INSERM U964, Université de Strasbourg, Illkirch 67400, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Thibault
authors.affiliation: Department of Translational medicine and neurogenetics, IGBMC, CNRS UMR7104, INSERM U964, Université de Strasbourg, Illkirch 67400, France.
authors.forename: Muriel
authors.initials: M
authors.lastname: Philipps
authors.affiliation: Department of Translational medicine and neurogenetics, IGBMC, CNRS UMR7104, INSERM U964, Université de Strasbourg, Illkirch 67400, France.
authors.forename: Serge
authors.initials: S
authors.lastname: Vicaire
authors.affiliation: Department of Translational medicine and neurogenetics, IGBMC, CNRS UMR7104, INSERM U964, Université de Strasbourg, Illkirch 67400, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Jost
authors.affiliation: Neuromuscular Research Center, Tampere University and University Hospital, Tampere 33520, Finland.|Department of Medical Genetics, Folkhälsan Institute of Genetics, Helsinki University, Helsinki 00250, Finland.|Department of Neurology, Vaasa Central Hospital, Vaasa 65130, Finland.
authors.forename: Bjarne
authors.initials: B
authors.lastname: Udd
authors.affiliation: Department of Neurology, Stanford University, Stanford, California 94304, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Day
authors.affiliation: Service de Cardiologie, Université Paris-Descartes, Hôpital Cochin, AP-HP, Paris 75014, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Duboc
authors.affiliation: Service de Cardiologie, Université Paris-Descartes, Hôpital Cochin, AP-HP, Paris 75014, France.
authors.forename: Karim
authors.initials: K
authors.lastname: Wahbi
authors.affiliation: Department of Neurology, Toneyama National Hospital, Toyonaka 560-8552, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Matsumura
authors.affiliation: Department of Neurology, Toneyama National Hospital, Toyonaka 560-8552, Japan.
authors.forename: Harutoshi
authors.initials: H
authors.lastname: Fujimura
authors.affiliation: Department of Neurology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
authors.forename: Hideki
authors.identifier: http://orcid.org/0000-0002-0874-7542
authors.initials: H
authors.lastname: Mochizuki
authors.affiliation: CNRS UMR7175, Ecole Supérieure de Biotechnologies de Strasbourg, Illkirch 67400, France.
authors.forename: François
authors.initials: F
authors.lastname: Deryckere
authors.affiliation: Division of Neurology, Hyogo Medical College, Nishinomiya 663-8501, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Laboratory of Structural Neuropathology, Doshisha University Graduate School of Brain Science, Kyoto 610-0394, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Nukina
authors.affiliation: Graduate School of Arts and Sciences, University of Tokyo, Tokyo 153-8902, Japan.
authors.forename: Shoichi
authors.initials: S
authors.lastname: Ishiura
authors.affiliation: Université Lyon 1, CNRS, UMR5558 LBBE, Villeurbanne 69622, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Lacroix
authors.affiliation: Hospices civils de Lyon, Laboratoire de cytogénétique constitutionelle, Bron 69500, France.
authors.forename: Amandine
authors.initials: A
authors.lastname: Campan-Fournier
authors.affiliation: Pôle Rhône Alpes de Bioinformatique, Université Lyon 1, Bâtiment Gregor Mendel, Villeurbanne 69100, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Navratil
authors.affiliation: Centre de Recherche en Cancérologie de Lyon, Lyon 69373, France.
authors.forename: Emilie
authors.identifier: http://orcid.org/0000-0003-1456-5347
authors.initials: E
authors.lastname: Chautard
authors.affiliation: Centre de Recherche en Cancérologie de Lyon, Lyon 69373, France.
authors.forename: Didier
authors.initials: D
authors.lastname: Auboeuf
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga Medical University, Otsu 520-2192, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Horie
authors.affiliation: Department of Information Physiology, National Institute for Physiological Sciences, Okazaki 444-8585, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Imoto
authors.affiliation: Department of Neurology, Chang Gung Memorial Hospital, Keelung 20401, Taiwan.
authors.forename: Kuang-Yung
authors.initials: KY
authors.lastname: Lee
authors.affiliation: Department of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, University of Florida, College of Medicine, Gainesville, Florida 32610, USA.
authors.forename: Maurice S
authors.initials: MS
authors.lastname: Swanson
authors.affiliation: Department of Neurology, Hospital Universitario DONOSTIA, Neuroscience Area, Institute Biodonostia CIBERNED and University of Basque Country UPV-EHU, San Sebastián 20014, Spain.
authors.forename: Adolfo Lopez
authors.initials: AL
authors.lastname: de Munain
authors.affiliation: Laboratory of Biomedical Sciences and Information Management, National Cerebral and Cardiovascular Center Research Institute, Osaka 565-8565, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Inada
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga Medical University, Otsu 520-2192, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Itoh
authors.affiliation: Laboratory of Biomedical Sciences and Information Management, National Cerebral and Cardiovascular Center Research Institute, Osaka 565-8565, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Nakazawa
authors.affiliation: Department of Cardiovascular and Respiratory Medicine, Shiga Medical University, Otsu 520-2192, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ashihara
authors.affiliation: Department of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, University of Florida, College of Medicine, Gainesville, Florida 32610, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Wang
authors.affiliation: Department of Physiology, Friedrich Schiller University Hospital, Jena 07743, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Zimmer
authors.affiliation: Sorbonne Universités UPMC Univ Paris 06, Inserm, CNRS, Centre de Recherche en Myologie UMRS974/FRE3617, Institut de Myologie, GH Pitié-Salpêtrière, Paris 75013, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Furling
authors.affiliation: Department of Neurology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
authors.forename: Masanori P
authors.initials: MP
authors.lastname: Takahashi
authors.affiliation: Department of Translational medicine and neurogenetics, IGBMC, CNRS UMR7104, INSERM U964, Université de Strasbourg, Illkirch 67400, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Charlet-Berguerand
mesh_terms: D000328:Adult; D000368:Aged; D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000150:complications* / Q000235:genetics*; D001483:Base Sequence; D001665:Binding Sites; D003198:Computer Simulation; D055724:Electrophysiological Phenomena; D005091:Exons / Q000235:genetics; D005260:Female; D057809:HEK293 Cells; D006329:Heart Conduction System / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009223:Myotonic Dystrophy / Q000150:complications* / Q000235:genetics*; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics* / Q000378:metabolism; D059372:Nucleotide Motifs / Q000235:genetics; D016601:RNA-Binding Proteins / Q000378:metabolism; D015222:Sodium Channels / Q000378:metabolism; D014981:Xenopus
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; D016601:RNA-Binding Proteins; C568320:SCN5A protein, human; D015222:Sodium Channels