Splicing misregulation of SCN5A contributes to cardiac-conduction delay and heart arrhythmia in myotonic dystrophy.
Fiche publication
Date publication
avril 2016
Journal
Nature communications
Auteurs
Membres identifiés du Cancéropôle Est :
Dr DERYCKERE Francois, Mme THIBAULT-CARPENTIER Christelle, Dr CHARLET BERGUERAND Nicolas
Tous les auteurs :
Freyermuth F, Rau F, Kokunai Y, Linke T, Sellier C, Nakamori M, Kino Y, Arandel L, Jollet A, Thibault C, Philipps M, Vicaire S, Jost B, Udd B, Day JW, Duboc D, Wahbi K, Matsumura T, Fujimura H, Mochizuki H, Deryckere F, Kimura T, Nukina N, Ishiura S, Lacroix V, Campan-Fournier A, Navratil V, Chautard E, Auboeuf D, Horie M, Imoto K, Lee KY, Swanson MS, Lopez de Munain A, Inada S, Itoh H, Nakazawa K, Ashihara T, Wang E, Zimmer T, Furling D, Takahashi MP, Charlet-Berguerand N
Lien Pubmed
Résumé
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.
Mots clés
Adult, Aged, Alternative Splicing, genetics, Animals, Arrhythmias, Cardiac, complications, Base Sequence, Binding Sites, Computer Simulation, Electrophysiological Phenomena, Exons, genetics, Female, HEK293 Cells, Heart Conduction System, pathology, Humans, Male, Middle Aged, Molecular Sequence Data, Myotonic Dystrophy, complications, NAV1.5 Voltage-Gated Sodium Channel, genetics, Nucleotide Motifs, genetics, RNA-Binding Proteins, metabolism, Sodium Channels, metabolism, Xenopus
Référence
Nat Commun. 2016 Apr;7:11067