title: RBM20, a gene for hereditary cardiomyopathy, regulates titin splicing.
abstract: 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.
authors.affiliation: Muscle Biology Laboratory, University of Wisconsin Madison, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Guo
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schafer
authors.forename: Marion L
authors.initials: ML
authors.lastname: Greaser
authors.forename: Michael H
authors.initials: MH
authors.lastname: Radke
authors.forename: Martin
authors.initials: M
authors.lastname: Liss
authors.forename: Thirupugal
authors.initials: T
authors.lastname: Govindarajan
authors.forename: Henrike
authors.initials: H
authors.lastname: Maatz
authors.forename: Herbert
authors.initials: H
authors.lastname: Schulz
authors.forename: Shijun
authors.initials: S
authors.lastname: Li
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Parrish
authors.forename: Vita
authors.initials: V
authors.lastname: Dauksaite
authors.forename: Padmanabhan
authors.initials: P
authors.lastname: Vakeel
authors.forename: Sabine
authors.initials: S
authors.lastname: Klaassen
authors.forename: Brenda
authors.initials: B
authors.lastname: Gerull
authors.forename: Ludwig
authors.initials: L
authors.lastname: Thierfelder
authors.forename: Vera
authors.initials: V
authors.lastname: Regitz-Zagrosek
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Hacker
authors.forename: Kurt W
authors.initials: KW
authors.lastname: Saupe
authors.forename: G William
authors.initials: GW
authors.lastname: Dec
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Ellinor
authors.forename: Calum A
authors.initials: CA
authors.lastname: MacRae
authors.forename: Bastian
authors.initials: B
authors.lastname: Spallek
authors.forename: Robert
authors.initials: R
authors.lastname: Fischer
authors.forename: Andreas
authors.initials: A
authors.lastname: Perrot
authors.forename: Cemil
authors.initials: C
authors.lastname: Özcelik
authors.forename: Kathrin
authors.initials: K
authors.lastname: Saar
authors.forename: Norbert
authors.initials: N
authors.lastname: Hubner
authors.forename: Michael
authors.initials: M
authors.lastname: Gotthardt
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D002311:Cardiomyopathy, Dilated / Q000235:genetics*; D064211:Connectin; D006801:Humans; D060588:LIM Domain Proteins / Q000235:genetics; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000235:genetics*; D009154:Mutation; D011494:Protein Kinases / Q000235:genetics*; D012326:RNA Splicing; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000502:physiology; D051381:Rats; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D064211:Connectin; C120696:LDB3 protein, human; D060588:LIM Domain Proteins; D009124:Muscle Proteins; C573837:RBM20 protein, rat; D016601:RNA-Binding Proteins; C577285:TTN protein, human; C543725:ribonucleic acid binding motif protein 20, human; D011494:Protein Kinases