Myotonic dystrophy, also known as Steinert disease, is the commonest adult form of muscular dystrophy. Patients affected by this genetic condition suffer from wasting of skeletal muscles as well as arrhythmia and other cardiac dysfunctions. This is a particularly debilitating disease, for which there is currently no treatment.
Myotonic dystrophy is due to a mutation leading to the expression of RNA containing long repetitive sequences of the CUG trinucleotide. These mutated RNAs accumulate and alter regulation of alternative splicing of numerous genes. Despite the significance of work already done on this disease, many points remain to be elucidated. This is true for the origin of arrhythmia and other cardiac dysfunctions, which represent the second most common cause of death in this disease.
In this new study, researchers have identified new splicing alterations in messenger RNA from heart samples of affected patients. Among these many alterations, biologists have established that those relating to the cardiac sodium channel (SCN5A) were fundamental to understanding the cardiac dysfunctions of these patients.
Scientists there clarified the molecular mechanisms leading to the alteration of SCN5A in these patients. Collaboration with Denis Furling’s team at the Institut de Myologie in Paris has enabled these cardiac alterations to be reproduced in a mouse model.
Alternative splicing model of the cardiac sodium channel (SCN5A) in myotonic dystrophy. (c) Inserm/IGBMC
This work was financed by the French Myopathy Association (AFM), the European research council (ERC), the European E-rare programme (ANR), Inserm and Labex-INRT (ANR).
 Institute of Genetics and Molecular and Cellular Biology (Inserm/CNRS/University of Strasbourg)
 In eukaryotes, this is a process by which RNA transcribed from a gene can undergo different cutting and splicing steps leading to the loss of various regions. This process enables proteins having distinct properties to be produced from the same gene.
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Splicing misregulation of SCN5A contributes to cardiac-conduction delay and heart arrhythmia in myotonic dystrophy Fernande Freyermuth1,*,w,Frederique Rau2,*, Yosuke Kokunai3, Thomas Linke4, Chantal Sellier1, Masayuki Nakamori3,Yoshihiro Kino5, Ludovic Arandel2, Arnaud Jollet2, Christelle Thibault1, Muriel Philipps1, Serge Vicaire1, Bernard Jost1,Bjarne Udd6,7,8, John W. Day9, Denis Duboc10, Karim Wahbi10, Tsuyoshi Matsumura11, Harutoshi Fujimura11,Hideki Mochizuki3, Franc ̧ois Deryckere12, Takashi Kimura13, Nobuyuki Nukina14, Shoichi Ishiura15, Vincent Lacroix16,Amandine Campan Fournier17, Vincent Navratil18, Emilie Chautard19, Didier Auboeuf19, Minoru Horie20, Keiji Imoto21,Kuang-Yung Lee22, Maurice S. Swanson23, Adolfo Lopez de Munain24, Shin Inada25, Hideki Itoh20, Kazuo Nakazawa25,Takashi Ashihara20, Eric Wang23, Thomas Zimmer4, Denis Furling2, Masanori P. Takahashi3 & Nicolas Charlet-Berguerand1 1 Department of Translational medicine and neurogenetics, IGBMC, CNRS UMR7104, INSERM U964, Université de Strasbourg, Illkirch 67400, France. 2Sorbonne Universités UPMC Univ Paris 06, Inserm, CNRS, Centre de Recherche en Myologie UMRS974/FRE3617, Institut de Myologie, GH Pitié-Salpêtrière, Paris 75013, France. 3Department of Neurology, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan. 4nDepartment of Physiology, Friedrich Schiller U niversity 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, Folkhalsan 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. 15Graduate School of Arts and Sciences, University of Tokyo , To k y o 1 5 3 - 8 9 0 2 , J a p a n . 16 Université Lyon 1, CNRS, UMR5558 LBBE, Villeurbanne 69622, France. 17Hospices civils de Lyon, Laboratoire de cytogénétique constitutionnelle, Bron 69500, France. 18Pole Rhône Alpes de Bio-informatique, Université Lyon 1, Bâtiment Gregor Mendel, Villeurbanne 69100, France. 19Centre de Recherche en Cancérologie deLyon,Lyon69373,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 CountryUPV-EHU, San Sebastian20014, Spain. 25 Laboratory of Biomedical Sciences and Information Management, National Cerebral and Cardiovascular Center Research Institute, Osaka 565-8565, Japan. * These authors contributed equally to the work Nature Communications, April 2016