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

Content Provider	PubMed Central
Author	Freyermuth, Fernande Rau, Frédérique Kokunai, Yosuke Linke, Thomas Sellier, Chantal Nakamori, Masayuki Kino, Yoshihiro Ludovic, Arandel 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 François, Deryckere Kimura, Takashi Nukina, Nobuyuki Ishiura, Shoichi Lacroix, Vincent Campan-fournier, Amandine Navratil, Vincent Chautard, Emilie Didier, Auboeuf Horie, Minoru Imoto, Keiji Lee, Kuang-yung Swanson, Maurice S. Munain, Adolfo Lopez De Inada, Shin Itoh, Hideki Nakazawa, Kazuo Ashihara, Takashi Wang, Eric Zimmer, Thomas Denis, Furling Takahashi, Masanori P. Nicolas, Charlet-berguerand
Copyright Year	2016
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.
Related Links	http://dx.doi.org/10.1038/ncomms11067
Starting Page	11067
File Format	PDF
ISSN	20411723
e-ISSN	20411723
Journal	Nature Communications
Volume Number	7
Language	English
Publisher	Nature Publishing Group
Publisher Date	2016-04-11
Access Restriction	Open
Rights Holder	Nature Publishing Group
Subject Keyword	Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Chemistry Physics and Astronomy Biochemistry, Genetics and Molecular Biology

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1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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