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)
1
IGBMC -
Institut de Génétique et de Biologie Moléculaire et Cellulaire
2 Institut de Myologie
3 Osaka University [Osaka]
4 Friedrich-Schiller-Universität = Friedrich Schiller University Jena [Jena, Germany]
5 Meiji Pharmaceutical University
6 University of Tampere [Finland]
7 Helsingin yliopisto = Helsingfors universitet = University of Helsinki
8 University of Vaasa
9 Stanford University
10 Service de Cardiologie [CHU Cochin]
11 Toneyama National Hospital
12 Intégrité du génome
13 Hyogo Medical College
14 Doshisha University [Kyoto]
15 UTokyo - The University of Tokyo
16 Baobab [LBBE]
17 Laboratoire de Cytogénétique Constitutionnelle [Hospices civils de Lyon]
18 PRABI - Pôle Rhône-Alpin de BioInformatique [Lyon]
19 UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon
20 Shiga University of Medical Science
21 National Institute for Physiological Science
22 CGMH - Chang Gung Memorial Hospital [Taipei]
23 UF - University of Florida [Gainesville]
24 Onekin [Donostia]
25 National cerebral and cardiovascular center research institute
2 Institut de Myologie
3 Osaka University [Osaka]
4 Friedrich-Schiller-Universität = Friedrich Schiller University Jena [Jena, Germany]
5 Meiji Pharmaceutical University
6 University of Tampere [Finland]
7 Helsingin yliopisto = Helsingfors universitet = University of Helsinki
8 University of Vaasa
9 Stanford University
10 Service de Cardiologie [CHU Cochin]
11 Toneyama National Hospital
12 Intégrité du génome
13 Hyogo Medical College
14 Doshisha University [Kyoto]
15 UTokyo - The University of Tokyo
16 Baobab [LBBE]
17 Laboratoire de Cytogénétique Constitutionnelle [Hospices civils de Lyon]
18 PRABI - Pôle Rhône-Alpin de BioInformatique [Lyon]
19 UNICANCER/CRCL - Centre de Recherche en Cancérologie de Lyon
20 Shiga University of Medical Science
21 National Institute for Physiological Science
22 CGMH - Chang Gung Memorial Hospital [Taipei]
23 UF - University of Florida [Gainesville]
24 Onekin [Donostia]
25 National cerebral and cardiovascular center research institute
Frédérique Rau
- Fonction : Auteur
- PersonId : 1178744
- IdHAL : frederique-rau
- ORCID : 0000-0001-7025-8144
- IdRef : 155891219
Ludovic Arandel
- Fonction : Auteur
- PersonId : 1179315
- IdHAL : ludovic-arandel
- IdRef : 272545201
Muriel Philipps
- Fonction : Auteur
- PersonId : 777705
- ORCID : 0000-0003-0108-6689
Bernard Jost
- Fonction : Auteur
- PersonId : 756812
- ORCID : 0000-0002-3722-3457
Vincent Lacroix
- Fonction : Auteur
- PersonId : 178908
- IdHAL : vincent-lacroix
- ORCID : 0000-0002-4235-8524
- IdRef : 130859583
Emilie Chautard
- Fonction : Auteur
- PersonId : 1528
- IdHAL : emilie-chautard
- ORCID : 0000-0003-1456-5347
- IdRef : 174803486
Didier Auboeuf
- Fonction : Auteur
- PersonId : 1147387
- ORCID : 0000-0002-3757-0002
- IdRef : 128682663
Denis Furling
Connectez-vous pour contacter l'auteur
- Fonction : Auteur correspondant
- PersonId : 744465
- IdHAL : denis-furling
- ORCID : 0000-0001-7912-4409
- IdRef : 167401556
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Nicolas Charlet-Berguerand
- Fonction : Auteur
- PersonId : 748210
- IdHAL : nicolas-charlet-berguerand
- ORCID : 0000-0002-4423-4920
- IdRef : 089052471
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.
| Origine | Publication financée par une institution |
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