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

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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 , J W , 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 , K-Y , Swanson , M S , Lopez de Munain , A , Inada , S , Itoh , H , Nakazawa , K , Ashihara , T , Wang , E , Zimmer , T , Furling , D , Takahashi , M P & Charlet-Berguerand , N 2016 , ' Splicing misregulation of SCN5A contributes to cardiac-conduction delay and heart arrhythmia in myotonic dystrophy ' , Nature Communications , vol. 7 , 11067 . https://doi.org/10.1038/ncomms11067

Title: Splicing misregulation of SCN5A contributes to cardiac-conduction delay and heart arrhythmia in myotonic dystrophy
Author: Freyermuth, Fernande; Rau, Frederique; Kokunai, Yosuke; Linke, Thomas; Sellier, Chantal; Nakamori, Masayuki; Kino, Yoshihiro; Arandel, Ludovic; Jollet, Arnaud; Thibault, Christelle; Philipps, Muriel; Vicaire, Serge; Jost, Bernard; Udd, Bjarne; Day, John W.; Duboc, Denis; Wahbi, Karim; Matsumura, Tsuyoshi; Fujimura, Harutoshi; Mochizuki, Hideki; Deryckere, Francois; Kimura, Takashi; Nukina, Nobuyuki; Ishiura, Shoichi; Lacroix, Vincent; Campan-Fournier, Amandine; Navratil, Vincent; Chautard, Emilie; Auboeuf, Didier; Horie, Minoru; Imoto, Keiji; Lee, Kuang-Yung; Swanson, Maurice S.; Lopez de Munain, Adolfo; Inada, Shin; Itoh, Hideki; Nakazawa, Kazuo; Ashihara, Takashi; Wang, Eric; Zimmer, Thomas; Furling, Denis; Takahashi, Masanori P.; Charlet-Berguerand, Nicolas
Contributor: University of Helsinki, Medicum
Date: 2016-04
Language: eng
Number of pages: 14
Belongs to series: Nature Communications
ISSN: 2041-1723
URI: http://hdl.handle.net/10138/161396
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.
Subject: PRE-MESSENGER-RNA
BRUGADA-SYNDROME
MUSCULAR-DYSTROPHY
MUSCLEBLIND PROTEINS
STRUCTURAL INSIGHTS
CHLORIDE CHANNEL
SKELETAL-MUSCLE
MOUSE MODEL
CTG REPEAT
TYPE-1
3111 Biomedicine
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