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XB-ART-52530
Nat Commun April 11, 2016; 7 11067.

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

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 .


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.

PubMed ID: 27063795
PMC ID: PMC4831019
Article link: Nat Commun
Grant support: [+]

Species referenced: Xenopus
Genes referenced: celf1 cnbp dmd.2 mbnl1 nav1 nodal rplp0 scn1b scn5a sh2b2 sod1 tgfb1


Article Images: [+] show captions
References [+] :
Algalarrondo, Abnormal sodium current properties contribute to cardiac electrical and contractile dysfunction in a mouse model of myotonic dystrophy type 1. 2015, Pubmed