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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.

SUBMITTER: Freyermuth F 

PROVIDER: S-EPMC4831019 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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

Freyermuth Fernande F   Rau Frédérique F   Kokunai Yosuke Y   Linke Thomas T   Sellier Chantal C   Nakamori Masayuki M   Kino Yoshihiro Y   Arandel Ludovic L   Jollet Arnaud A   Thibault Christelle C   Philipps Muriel M   Vicaire Serge S   Jost Bernard B   Udd Bjarne B   Day John W JW   Duboc Denis D   Wahbi Karim K   Matsumura Tsuyoshi T   Fujimura Harutoshi H   Mochizuki Hideki H   Deryckere François F   Kimura Takashi T   Nukina Nobuyuki N   Ishiura Shoichi S   Lacroix Vincent V   Campan-Fournier Amandine A   Navratil Vincent V   Chautard Emilie E   Auboeuf Didier D   Horie Minoru M   Imoto Keiji K   Lee Kuang-Yung KY   Swanson Maurice S MS   de Munain Adolfo Lopez AL   Inada Shin S   Itoh Hideki H   Nakazawa Kazuo K   Ashihara Takashi T   Wang Eric E   Zimmer Thomas T   Furling Denis D   Takahashi Masanori P MP   Charlet-Berguerand Nicolas N  

Nature communications 20160411


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 fi  ...[more]

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