New Insights in RBM20 Cardiomyopathy

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Abstract

Purpose of Review

This review aims to give an update on recent findings related to the cardiac splicing factor RNA-binding motif protein 20 (RBM20) and RBM20 cardiomyopathy, a form of dilated cardiomyopathy caused by mutations in RBM20.

Recent Findings

While most research on RBM20 splicing targets has focused on titin ( TTN), multiple studies over the last years have shown that other splicing targets of RBM20 including Ca ²⁺/calmodulin-dependent kinase IIδ ( CAMK2D) might be critically involved in the development of RBM20 cardiomyopathy. In this regard, loss of RBM20 causes an abnormal intracellular calcium handling, which may relate to the arrhythmogenic presentation of RBM20 cardiomyopathy. In addition, RBM20 presents clinically in a highly gender-specific manner, with male patients suffering from an earlier disease onset and a more severe disease progression.

Summary

Further research on RBM20, and treatment of RBM20 cardiomyopathy, will need to consider both the multitude and relative contribution of the different splicing targets and related pathways, as well as gender differences.

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Most cited references 89

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Epidemiology of heart failure: the prevalence of heart failure and ventricular dysfunction in older adults over time. A systematic review.

Evelien E S van Riet, Arno Hoes, Kim Wagenaar … (2016)

The 'epidemic' of heart failure seems to be changing, but precise prevalence estimates of heart failure and left ventricular dysfunction (LVD) in older adults, based on adequate echocardiographic assessment, are scarce. Systematic reviews including recent studies on the prevalence of heart failure and LVD are lacking. We aimed to assess the trends in the prevalence of LVD, and heart failure with reduced (HFrEF) and preserved ejection fraction (HFpEF) in the older population at large. A systematic electronic search of the databases Medline and Embase was performed. Studies that reported prevalence estimates in community-dwelling people ≥60 years old were included if echocardiography was used to establish the diagnosis. In total, 28 articles from 25 different study populations were included. The median prevalence of systolic and 'isolated' diastolic LVD was 5.5% (range 3.3-9.2%) and 36.0% (range 15.8-52.8%), respectively. A peak in systolic dysfunction prevalence seems to have occurred between 1995 and 2000. 'All type' heart failure had a median prevalence rate of 11.8% (range 4.7-13.3%), with fairly stable rates in the last decade and with HFpEF being more common than HFrEF [median prevalence 4.9% (range 3.8-7.4%) and 3.3% (range 2.4-5.8%), respectively]. Both LVD and heart failure remain common in the older population at large. The prevalence of diastolic dysfunction is on the rise and currently higher than that of systolic dysfunction. The prevalence of the latter seems to have decreased in the 21st century.

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RBM20, a gene for hereditary cardiomyopathy, regulates titin splicing.

Wei. Guo, Sebastian Schafer, Marion L. Greaser … (2012)

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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Deep sequencing of subcellular RNA fractions shows splicing to be predominantly co-transcriptional in the human genome but inefficient for lncRNAs

Hagen Tilgner, David G. Knowles, Rory Johnson … (2012)

Splicing remains an incompletely understood process. Recent findings suggest that chromatin structure participates in its regulation. Here, we analyze the RNA from subcellular fractions obtained through RNA-seq in the cell line K562. We show that in the human genome, splicing occurs predominantly during transcription. We introduce the coSI measure, based on RNA-seq reads mapping to exon junctions and borders, to assess the degree of splicing completion around internal exons. We show that, as expected, splicing is almost fully completed in cytosolic polyA+ RNA. In chromatin-associated RNA (which includes the RNA that is being transcribed), for 5.6% of exons, the removal of the surrounding introns is fully completed, compared with 0.3% of exons for which no intron-removal has occurred. The remaining exons exist as a mixture of spliced and fewer unspliced molecules, with a median coSI of 0.75. Thus, most RNAs undergo splicing while being transcribed: “co-transcriptional splicing.” Consistent with co-transcriptional spliceosome assembly and splicing, we have found significant enrichment of spliceosomal snRNAs in chromatin-associated RNA compared with other cellular RNA fractions and other nonspliceosomal snRNAs. CoSI scores decrease along the gene, pointing to a “first transcribed, first spliced” rule, yet more downstream exons carry other characteristics, favoring rapid, co-transcriptional intron removal. Exons with low coSI values, that is, in the process of being spliced, are enriched with chromatin marks, consistent with a role for chromatin in splicing during transcription. For alternative exons and long noncoding RNAs, splicing tends to occur later, and the latter might remain unspliced in some cases.

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Author and article information

Contributors

M. M. G. van den Hoogenhof: maarten.vandenhoogenhof@med.uni-heidelberg.de

Journal

Journal ID (nlm-ta): Curr Heart Fail Rep

Journal ID (iso-abbrev): Curr Heart Fail Rep

Title: Current Heart Failure Reports

Publisher: Springer US (New York )

ISSN (Print): 1546-9530

ISSN (Electronic): 1546-9549

Publication date (Electronic): 13 August 2020

Publication date PMC-release: 13 August 2020

Publication date (Print): 2020

Volume: 17

Issue: 5

Pages: 234-246

Affiliations

[1 ]GRID grid.5253.1, ISNI 0000 0001 0328 4908, Institute of Experimental Cardiology, , Heidelberg University Hospital, ; Heidelberg, Germany

[2 ]DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany

Article

Publisher ID: 475

DOI: 10.1007/s11897-020-00475-x

PMC ID: 7495990

PubMed ID: 32789749

SO-VID: d2454877-78b6-4ee6-8c65-5522ba533ac9

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Funding

Funded by: Universitätsklinikum Heidelberg (8914)

Open Access :

Open Access funding provided by Projekt DEAL.

Custom metadata

ScienceOpen disciplines: Cardiovascular Medicine

Keywords: rbm20,dilated cardiomyopathy,camkiiδ,calcium handling,gender differences,titin

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ScienceOpen disciplines: Cardiovascular Medicine

Keywords: rbm20, dilated cardiomyopathy, camkiiδ, calcium handling, gender differences, titin

New Insights in RBM20 Cardiomyopathy

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Abstract

Purpose of Review

Recent Findings

Summary

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Karger: Digital Health

Most cited references 89

Epidemiology of heart failure: the prevalence of heart failure and ventricular dysfunction in older adults over time. A systematic review.

RBM20, a gene for hereditary cardiomyopathy, regulates titin splicing.

Deep sequencing of subcellular RNA fractions shows splicing to be predominantly co-transcriptional in the human genome but inefficient for lncRNAs

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