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

Fernande Freyermuth 1 Frédérique Rau 2 Yosuke Kokunai 3 Thomas Linke 4 Chantal Sellier 1 Masayuki Nakamori 3 Yoshihiro Kino 5 Ludovic Arandel 2 Arnaud Jollet 2 Christelle Thibault 1 Muriel Philipps 1 Serge Vicaire 1 Bernard Jost 1 Bjarne Udd 6, 7, 8 John W Day 9 Denis Duboc 10 Karim Wahbi 10 Tsuyoshi Matsumura 11 Harutoshi Fujimura 11 Hideki Mochizuki 3 François Deryckere 12 Takashi Kimura 13 Nobuyuki Nukina 14 Shoichi Ishiura 15 Vincent Lacroix 16 Amandine Campan-Fournier 17 Vincent Navratil 18 Emilie Chautard 19 Didier Auboeuf 19 Minoru Horie 20 Keiji Imoto 21 Kuang-Yung Lee 22 Maurice S. Swanson 23 Adolfo López de Munain 24 Shin Inada 25 Hideki Itoh 20 Kazuo Nakazawa 25 Takashi Ashihara 20 Eric Wang 23 Thomas Zimmer 4 Denis Furling 2, * Masanori P Takahashi 3 Nicolas Charlet-Berguerand 1
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.
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Fernande Freyermuth, Frédérique Rau, Yosuke Kokunai, Thomas Linke, Chantal Sellier, et al.. Splicing misregulation of SCN5A contributes to cardiac-conduction delay and heart arrhythmia in myotonic dystrophy. Nature Communications, Nature Publishing Group, 2016, 7, pp.11067. ⟨10.1038/ncomms11067⟩. ⟨hal-01301863⟩

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