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

Fernande Freyermuth; Frédérique Rau; Yosuke Kokunai; Thomas Linke; Chantal Sellier; Masayuki Nakamori; Yoshihiro Kino; Ludovic Arandel; Arnaud Jollet; Christelle Thibault; Muriel Philipps; Serge Vicaire; Bernard Jost; Bjarne Udd; John W. Day; Denis Duboc; Karim Wahbi; Tsuyoshi Matsumura; Harutoshi Fujimura; Hideki Mochizuki; François Deryckere; Takashi Kimura; Nobuyuki Nukina; Shoichi Ishiura; Vincent Lacroix; Amandine Campan-Fournier; Vincent Navratil; Emilie Chautard; Didier Auboeuf; Minoru Horie; Keiji Imoto; Kuang Yung Lee; Maurice S. Swanson; Adolfo Lopez De Munain; Shin Inada; Hideki Itoh; Kazuo Nakazawa; Takashi Ashihara; Eric Wang; Thomas Zimmer; Denis Furling; Masanori P. Takahashi; Nicolas Charlet-Berguerand

doi:10.1038/ncomms11067

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

Fernande Freyermuth
, Frédérique Rau
, Yosuke Kokunai
, Thomas Linke
, Chantal Sellier
, Masayuki Nakamori
, Yoshihiro Kino
, Ludovic Arandel
, Arnaud Jollet
, Christelle Thibault
, Muriel Philipps
, Serge Vicaire
, Bernard Jost
, Bjarne Udd
, John W. Day
, Denis Duboc
, Karim Wahbi
, Tsuyoshi Matsumura
, Harutoshi Fujimura
, Hideki Mochizuki

François Deryckere, Takashi Kimura, Nobuyuki Nukina, Shoichi Ishiura, Vincent Lacroix, Amandine Campan-Fournier, Vincent Navratil, Emilie Chautard, Didier Auboeuf, Minoru Horie, Keiji Imoto, Kuang Yung Lee, Maurice S. Swanson, Adolfo Lopez De Munain, Shin Inada, Hideki Itoh, Kazuo Nakazawa, Takashi Ashihara, Eric Wang, Thomas Zimmer, Denis Furling^*, Masanori P. Takahashi, Nicolas Charlet-Berguerand

^*Corresponding author for this work

Université de Strasbourg
Massachusetts General Hospital
Sorbonne Universités
The University of Osaka
Friedrich Schiller University Jena
Meiji Pharmaceutical University
Tampere University
University of Helsinki
Vaasa Hospital District
Stanford University
Université Paris Cité
National Hospital Organization Osaka Toneyama Medical Center
CNRS
Hyogo Medical University
Doshisha University
The University of Tokyo
Université Lyon 1
Hospices civils de Lyon
Universite Claude Bernard Lyon 1
INSERM U1052
Shiga University of Medical Science
National Institutes of Natural Sciences - National Institute for Physiological Sciences
Chang Gung Memorial Hospital
University of Florida
Hospital Universitario Donostia
National Cerebral and Cardiovascular Center

Research output: Contribution to journal › Journal Article › peer-review

176 Scopus citations

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.

Original language	English
Article number	11067
Journal	Nature Communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms11067
State	Published - 11 04 2016
Externally published	Yes

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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., ... Charlet-Berguerand, N. (2016). Splicing misregulation of SCN5A contributes to cardiac-conduction delay and heart arrhythmia in myotonic dystrophy. Nature Communications, 7, Article 11067. https://doi.org/10.1038/ncomms11067

@article{0813c706c2e24e70818e1997219fb5a4,

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

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.",

author = "Fernande Freyermuth and Fr{\'e}d{\'e}rique Rau and Yosuke Kokunai and Thomas Linke and Chantal Sellier and Masayuki Nakamori and Yoshihiro Kino and Ludovic Arandel and Arnaud Jollet and Christelle Thibault and Muriel Philipps and Serge Vicaire and Bernard Jost and Bjarne Udd and Day, \{John W.\} and Denis Duboc and Karim Wahbi and Tsuyoshi Matsumura and Harutoshi Fujimura and Hideki Mochizuki and Fran{\c c}ois Deryckere and Takashi Kimura and Nobuyuki Nukina and Shoichi Ishiura and Vincent Lacroix and Amandine Campan-Fournier and Vincent Navratil and Emilie Chautard and Didier Auboeuf and Minoru Horie and Keiji Imoto and Lee, \{Kuang Yung\} and Swanson, \{Maurice S.\} and \{De Munain\}, \{Adolfo Lopez\} and Shin Inada and Hideki Itoh and Kazuo Nakazawa and Takashi Ashihara and Eric Wang and Thomas Zimmer and Denis Furling and Takahashi, \{Masanori P.\} and Nicolas Charlet-Berguerand",

year = "2016",

month = apr,

day = "11",

doi = "10.1038/ncomms11067",

language = "英语",

volume = "7",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

}

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, De Munain, AL, Inada, S, Itoh, H, Nakazawa, K, Ashihara, T, Wang, E, Zimmer, T, Furling, D, Takahashi, MP & 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

TY - JOUR

T1 - Splicing misregulation of SCN5A contributes to cardiac-conduction delay and heart arrhythmia in myotonic dystrophy

AU - Freyermuth, Fernande

AU - Rau, Frédérique

AU - Kokunai, Yosuke

AU - Linke, Thomas

AU - Sellier, Chantal

AU - Nakamori, Masayuki

AU - Kino, Yoshihiro

AU - Arandel, Ludovic

AU - Jollet, Arnaud

AU - Thibault, Christelle

AU - Philipps, Muriel

AU - Vicaire, Serge

AU - Jost, Bernard

AU - Udd, Bjarne

AU - Day, John W.

AU - Duboc, Denis

AU - Wahbi, Karim

AU - Matsumura, Tsuyoshi

AU - Fujimura, Harutoshi

AU - Mochizuki, Hideki

AU - Deryckere, François

AU - Kimura, Takashi

AU - Nukina, Nobuyuki

AU - Ishiura, Shoichi

AU - Lacroix, Vincent

AU - Campan-Fournier, Amandine

AU - Navratil, Vincent

AU - Chautard, Emilie

AU - Auboeuf, Didier

AU - Horie, Minoru

AU - Imoto, Keiji

AU - Lee, Kuang Yung

AU - Swanson, Maurice S.

AU - De Munain, Adolfo Lopez

AU - Inada, Shin

AU - Itoh, Hideki

AU - Nakazawa, Kazuo

AU - Ashihara, Takashi

AU - Wang, Eric

AU - Zimmer, Thomas

AU - Furling, Denis

AU - Takahashi, Masanori P.

AU - Charlet-Berguerand, Nicolas

PY - 2016/4/11

Y1 - 2016/4/11

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/84964334537

U2 - 10.1038/ncomms11067

DO - 10.1038/ncomms11067

M3 - 文章

C2 - 27063795

AN - SCOPUS:84964334537

SN - 2041-1723

VL - 7

JO - Nature Communications

JF - Nature Communications

M1 - 11067

ER -

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

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