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Nat Commun. 2016 Apr 11;7:11067. doi: 10.1038/ncomms11067.

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

Author information

1
Department of Translational medicine and neurogenetics, IGBMC, CNRS UMR7104, INSERM U964, Université de Strasbourg, Illkirch 67400, France.
2
Sorbonne Universités UPMC Univ Paris 06, Inserm, CNRS, Centre de Recherche en Myologie UMRS974/FRE3617, Institut de Myologie, GH Pitié-Salpêtrière, Paris 75013, France.
3
Department of Neurology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
4
Department of Physiology, Friedrich Schiller University Hospital, Jena 07743, Germany.
5
Department of Bioinformatics and Molecular Neuropathology, Meiji Pharmaceutical University, Kiyose 205-8588, Japan.
6
Neuromuscular Research Center, Tampere University and University Hospital, Tampere 33520, Finland.
7
Department of Medical Genetics, Folkhälsan Institute of Genetics, Helsinki University, Helsinki 00250, Finland.
8
Department of Neurology, Vaasa Central Hospital, Vaasa 65130, Finland.
9
Department of Neurology, Stanford University, Stanford, California 94304, USA.
10
Service de Cardiologie, Université Paris-Descartes, Hôpital Cochin, AP-HP, Paris 75014, France.
11
Department of Neurology, Toneyama National Hospital, Toyonaka 560-8552, Japan.
12
CNRS UMR7175, Ecole Supérieure de Biotechnologies de Strasbourg, Illkirch 67400, France.
13
Division of Neurology, Hyogo Medical College, Nishinomiya 663-8501, Japan.
14
Laboratory of Structural Neuropathology, Doshisha University Graduate School of Brain Science, Kyoto 610-0394, Japan.
15
Graduate School of Arts and Sciences, University of Tokyo, Tokyo 153-8902, Japan.
16
Université Lyon 1, CNRS, UMR5558 LBBE, Villeurbanne 69622, France.
17
Hospices civils de Lyon, Laboratoire de cytogénétique constitutionelle, Bron 69500, France.
18
Pôle Rhône Alpes de Bioinformatique, Université Lyon 1, Bâtiment Gregor Mendel, Villeurbanne 69100, France.
19
Centre de Recherche en Cancérologie de Lyon, Lyon 69373, France.
20
Department of Cardiovascular and Respiratory Medicine, Shiga Medical University, Otsu 520-2192, Japan.
21
Department of Information Physiology, National Institute for Physiological Sciences, Okazaki 444-8585, Japan.
22
Department of Neurology, Chang Gung Memorial Hospital, Keelung 20401, Taiwan.
23
Department of Molecular Genetics and Microbiology, Center for NeuroGenetics and the Genetics Institute, University of Florida, College of Medicine, Gainesville, Florida 32610, USA.
24
Department of Neurology, Hospital Universitario DONOSTIA, Neuroscience Area, Institute Biodonostia CIBERNED and University of Basque Country UPV-EHU, San Sebastián 20014, Spain.
25
Laboratory of Biomedical Sciences and Information Management, National Cerebral and Cardiovascular Center Research Institute, Osaka 565-8565, Japan.

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.

PMID:
27063795
PMCID:
PMC4831019
DOI:
10.1038/ncomms11067
[Indexed for MEDLINE]
Free PMC Article
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