RBM20, a gene for hereditary cardiomyopathy, regulates titin splicing
Open accessAbstract
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.
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SORBS1 and MAP4K4 had multiple noncanonical isoforms that were detectable across multiple tissues, whereas titin had the most isoforms identified.
“A number of proteins including SORBS1 and MAP4K4 had multiple noncanonical isoforms that were detectable across multiple tissues, whereas the protein with the most isoforms identified was titin (Figure 3A), which is also the largest protein in the human genome with the most exons and whose splicing has been widely implicated in congenital heart diseases (Guo et al., 2012; Herman et al., 2012).”
From Splice-Junction-Based Mapping of Alternative Isoforms in the Human Proteome (2019) · cites this paper as Guo et al., 2012
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- Authors
- Guo, W., Schafer, S., Greaser, M. L., Radke, M. H., Liss, M., Govindarajan, T., Maatz, H., Schulz, H., Li, S., Parrish, A. M., Dauksaite, V., Vakeel, P., Klaassen, S., Gerull, B., Thierfelder, L., Regitz-Zagrosek, V., Hacker, T. A., Saupe, K. W., Dec, G. W., Ellinor, P. T., MacRae, C. A., Spallek, B., Fischer, R., Perrot, A., Özcelik, C., Saar, K., Hubner, N., & Gotthardt, M.
- Affiliations
- University of Wisconsin–Madison (US)
- Max Delbrück Center (DE)
- Massachusetts General Hospital (US)
- Charité – Universitätsmedizin Berlin (DE)
- Corresponding author
- Gotthardt, Michael
- ORCID
- Venue
- Nature Medicine
- Published
- 2012-04-01
- Volume
- 18
- Issue
- 5
- Pages
- 766-773
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC3569865
- OpenAlex
- W2059060273
- Cited by
- 589
- References
- 52
- Citations by year
- 2026: 40 · 2025: 54 · 2024: 52 · 2023: 39 · 2022: 43 · 2021: 58 · 2020: 41 · 2019: 44 · 2018: 46 · 2017: 44 · 2016: 39 · 2015: 23 · 2014: 23 · 2013: 31 · 2012: 11
- FWCI
- 11.30
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL77196, R01HL077196, HL075431, R01HL075431)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Keywords
- RBM20, titin, alternative splicing, dilated cardiomyopathy, familial cardiomyopathy, splicing factors, titin isoforms, sarcomere, cardiac transcriptome, post-transcriptional regulation, heart failure, positional cloning, ion homeostasis
- MeSH terms
- Animals, Base Sequence, Cardiomyopathy, Dilated, Humans, Molecular Sequence Data, Muscle Proteins, Mutation, Protein Kinases, Rats, Inbred BN, Rats, Inbred F344, RNA Splicing, RNA-Binding Proteins, Adaptor Proteins, Signal Transducing, Rats, LIM Domain Proteins, Connectin
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