Abstract
Splice regulators play an essential role in the transcriptomic diversity of all eukaryotic cell types and organ systems. Recent evidence suggests a contribution of splice-regulatory networks in many diseases, such as cardiomyopathies. Adaptive splice regulators, such as RNA-binding motif protein 20 (RBM20) determine the physiological mRNA landscape formation, and rare variants in the RBM20 gene explain up to 6% of genetic dilated cardiomyopathy (DCM) cases. With ample knowledge from RBM20-deficient mice, rats, swine and induced pluripotent stem cells (iPSCs), the downstream targets and quantitative effects on splicing are now well-defined and the prerequisites for corrective therapeutic approaches are set. This review article highlights some of the recent advances in the field, ranging from aspects of granule formation to 3D genome architectures underlying RBM20-related cardiomyopathy. Promising therapeutic strategies are presented and put into context with the pathophysiological characteristics of RBM20-related diseases.
Highlights
DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg, 69120 Heidelberg, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, 10117 Berlin, Germany; Neuromuscular and Cardiovascular Cell Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany
Results from a study focusing on RNA-binding motif protein 20 (RBM20) variants responsible for arrhythmogenic cardiomyopathy proposed that affected patients should be clinically viewed similar to other arrhythmogenic cardiomyopathy or catecholaminergic polymorphic ventricular tachycardia (CPVT), which is caused by mutations in the
These insights into theThe mechanistic the disease is around the mid-fourth to fifth life decade and might become apparent to interactions provide a basis for the future development of RBM20 modulatorsdue which heart failure or arrhythmia [5]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Variants affecting the RRM-domain have not been frequently identified as causes for human RBM20-related cardiomyopathy, it has been observed that the knockout of the RRM-domain by deletion of exons 6 and 7, both in homozygous and heterozygous KO mice, affected alternative splicing of RBM200 s target genes, such as CAMK2D and LDB3 [30]. As controls, they used RYR2-isoform ratios from non-failing and DCM heart samples (both negative controls), along with positive controls derived from individuals carrying the proven pathogenic RBM20-p.Pro638Leu variant. They used RYR2-isoform ratios from non-failing and DCM heart samples (both negative controls), along with positive controls derived from individuals carrying the proven pathogenic RBM20-p.Pro638Leu variant Analogous to this, they investigated the ratio of TTN-N2B to total Titin as an additional classification tool and concluded that this ratio, on the contrary, is lowered in individuals carrying pathogenic.
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