New Insights in RBM20 Cardiomyopathy
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TRANSLATIONAL RESEARCH IN HEART FAILURE (J BACKS & M VAN DEN HOOGENHOF, SECTION EDITORS)
New Insights in RBM20 Cardiomyopathy D. Lennermann 1,2 & J. Backs 1,2 & M. M. G. van den Hoogenhof 1,2
# The Author(s) 2020
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 Ca2+/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. Keywords RBM20 . Dilated cardiomyopathy . CaMKIIδ . Calcium handling . Gender differences . Titin
Introduction Dilated cardiomyopathy (DCM), as defined by left ventricular or biventricular systolic dysfunction and dilatation that are not explained by abnormal loading conditions or coronary artery disease, is a leading cause of death worldwide, and one of the main reasons for heart transplantation [1]. Its prevalence has long been thought to be around 1:2500 based on a study in Olmsted county (USA) published in 1989, but newer studies estimate it up to 1:250 [2, 3]. The European Society of Cardiology divides DCM into familial (genetic) and nonfamilial (non-genetic) forms, with 30–50% of cases being familial in nature [4, 5]. In contrast to hypertrophic cardiomyopathy (HCM) and arrhythmogenic right ventricular cardiomyopathy This article is part of the Topical Collection on Translational Research in Heart Failure * M. M. G. van den Hoogenhof [email protected] 1
Institute of Experimental Cardiology, Heidelberg University Hospital, Heidelberg, Germany
2
DZHK (German Center for Cardiovascular Research), Partner Site Heidelberg/Mannheim, Heidelberg, Germany
(ARVC), where a small number of genes account for most of the genetic causes, DCM-causing mutations have been observed in a variety of genes of diverse ontology [2]. One of these genes is RBM20, of which mutations have been observed in 2–3% of familial DCM cases, and which interestingly has been shown to account for a number of DCM cases for which previously no genetic cause could be established [5–8]. The RBM20 gene encodes RNA binding motif protein 20, a trans-acting splicing factor [7]. RBM20 is highly expressed in striated muscle, e
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