Splicing misregulation of SCN5A contributes to cardiac-conduction delay and heart arrhythmia in myotonic dystrophy.
Splicing misregulation of SCN5A contributes to cardiac-conduction delay and heart arrhythmia in myotonic dystrophy.
复制标题
DOI：
10.1038/ncomms11067
复制
发表时间：
2016-04-11
影响因子：
16.6
通讯作者：
Charlet-Berguerand N
中科院分区：
文献类型：
--
作者：
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
肌强直性营养不良（DM）是由含有扩增CUG重复序列的突变rna表达引起的，这些重复序列隔离了肌盲样（MBNL）蛋白，导致选择性剪接改变。以传导延迟和心律失常为特征的心脏改变是糖尿病死亡的第二大常见原因。通过RNA测序，我们在糖尿病心脏样本中发现了新的剪接改变，包括心脏钠通道SCN5A中从成人外显子6B向胎儿外显子6A的转换。我们发现MBNL1调节SCN5A mRNA的选择性剪接，并且与对照成人亚型相比，DM中产生的SCN5A剪接变体的兴奋性降低。重要的是，在小鼠中复制Scn5a剪接改变足以促进心律失常和心传导延迟，这是肌强直性营养不良的两个主要特征。总之，SCN5A选择性剪接的错误调节可能导致肌强直性营养不良中观察到的一部分心功能障碍。肌强直性营养不良（MD）患者患有严重的心脏问题，原因不明。Freyermuth等人的研究表明，心脏Na+通道SCN5A转录物选择性剪接的错误调节，导致其胎儿形式的表达，可能会导致MD患者和小鼠心脏电生理特性的致命变化。
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. Patients with myotonic dystrophy (MD) suffer from severe cardiac issues of unknown aetiology. Freyermuth et al. show that fatal changes in cardiac electrophysiological properties in humans and mice with MD may arise from misregulation of the alternative splicing of the cardiac Na+ channel SCN5A transcript, resulting in expression of its fetal form.