RBM20, a gene for hereditary cardiomyopathy, regulates titin splicing

被引：429

作者：

Guo, Wei ^{[2
]}

Schafer, Sebastian ^{[1
]}

Greaser, Marion L. ^{[2
]}

Radke, Michael H. ^{[1
]}

Liss, Martin ^{[1
]}

Govindarajan, Thirupugal ^{[1
]}

Maatz, Henrike ^{[1
]}

Schulz, Herbert ^{[1
]}

Li, Shijun ^{[2
]}

Parrish, Amanda M. ^{[2
]}

Dauksaite, Vita ^{[1
]}

Vakeel, Padmanabhan ^{[1
]}

Klaassen, Sabine ^{[1
]}

Gerull, Brenda ^{[1
]}

Thierfelder, Ludwig ^{[1
]}

Regitz-Zagrosek, Vera ^{[3
,4
]}

Hacker, Timothy A. ^{[5
]}

Saupe, Kurt W. ^{[5
]}

Dec, G. William ^{[6
]}

Ellinor, Patrick T. ^{[6
]}

MacRae, Calum A. ^{[6
]}

Spallek, Bastian ^{[7
]}

Fischer, Robert ^{[7
]}

Perrot, Andreas ^{[8
]}

Oezcelik, Cemil ^{[8
]}

Saar, Kathrin ^{[1
]}

Hubner, Norbert ^{[1
]}

Gotthardt, Michael ^{[1
]}

机构：

[1] Max Delbruck Ctr Mol Med, Berlin, Germany

[2] Univ Wisconsin, Muscle Biol Lab, Madison, WI 53706 USA

[3] Univ Med Berlin, Charite, Cardiovasc Res Ctr, Berlin, Germany

[4] Univ Med Berlin, Charite, Inst Gender Med, Berlin, Germany

[5] Univ Wisconsin, Dept Med, Madison, WI USA

[6] Massachusetts Gen Hosp, Div Cardiol, Charlestown, MA USA

[7] Univ Med Berlin, Charite, Univ Kilikum Benjamin Franklin, Berlin, Germany

[8] Charite, Campus Virchow Klinikum, Dept Cardiol, D-13353 Berlin, Germany

来源：

NATURE MEDICINE | 2012年 / 18卷 / 05期

基金：

美国国家卫生研究院; 欧洲研究理事会;

关键词：

FAMILIAL DILATED CARDIOMYOPATHY; RNA-BINDING PROTEINS; ISOFORM EXPRESSION; PASSIVE STIFFNESS; HEART-FAILURE; SR PROTEINS; DISEASE; MUTATIONS; RAT; MYOCARDIUM;

D O I：

10.1038/nm.2693

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Alternative splicing has a major role in cardiac adaptive responses, as exemplified by the isoform switch of the sarcomeric protein titin, which adjusts ventricular filling. By positional cloning using a previously characterized rat strain with altered titin mRNA splicing, we identified a loss-of-function mutation in the gene encoding RNA binding motif protein 20 (Rbm20) as the underlying cause of pathological titin isoform expression. The phenotype of Rbm20-deficient rats resembled the pathology seen in individuals with dilated cardiomyopathy caused by RBM20 mutations. Deep sequencing of the human and rat cardiac transcriptome revealed an RBM20-dependent regulation of alternative splicing. In addition to titin (TTN), we identified a set of 30 genes with conserved splicing regulation between humans and rats. This network is enriched for genes that have previously been linked to cardiomyopathy, ion homeostasis and sarcomere biology. Our studies emphasize the key role of post-transcriptional regulation in cardiac function and provide mechanistic insights into the pathogenesis of human heart failure.

引用

页码：766 / U162

页数：9

共 51 条

[1] A Cypher/ZASP mutation associated with dilated cardiomyopathy alters the binding affinity to protein kinase C [J].