RBM20S639G mutation is a high genetic risk factor for premature death through RNA-protein condensates. (April 2022)

• Record Type: Journal Article
• Authors: Wang, Chunyan; Zhang, Yanghai; Methawasin, Mei; Braz, Camila Urbano; Gao-Hu, Jeffrey; Yang, Betty; Strom, Joshua; Gohlke, Jochen; Hacker, Timothy; Khatib, Hasan; Granzier, Henk; Guo, Wei
• Is Part Of: Journal of molecular and cellular cardiology. Volume 165(2022)
• Page Start: 115
• Page End: 129
• Publication Date: 2022-04
• Subjects: RBM20 mutation -- Protein condensates -- RNP granules -- Cardiomyopathy -- Heart failure -- Premature death; ANP atrial natriuretic peptide -- BNP brain natriuretic peptide -- DCM dilated cardiomyopathy -- FS fractional shortening -- FFI fura-2 fluorescence intensity -- RBP RNA binding protein -- RBM20 RNA binding motif protein 20 -- RMA robust multi-array analysis -- RNP ribonucleoprotein -- LV left ventricle -- LVDd left ventricular end diastolic dimension -- LVDs left ventricular end systolic dimension -- LVPWd left ventricular end diastolic posterior wall dimension -- LVPWs left ventricular end systolic posterior wall dimension -- GO Gene Ontology -- SDS-VAGE sodium dodecyl sulfate vertical agarose gel electrophoresis -- WT wild type -- HT heterozygous mutation -- HM homozygous mutation -- H&E staining Hematoxylin and eosin staining -- RS domain arginine and serine-rich domain -- ED-SSLR end diastolic-stress sarcomere length relation -- ES-SSLR end systolic-stress sarcomere length -- SL sarcomere length; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2022.01.004
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: Dilated cardiomyopathy (DCM) is a heritable and genetically heterogenous disease often idiopathic and a leading cause of heart failure with high morbidity and mortality. DCM caused by RNA binding motif protein 20 (RBM20) mutations is diverse and needs a more complete mechanistic understanding. RBM20 mutation S637G (S639G in mice) is linked to severe DCM and early death in human patients. In this study, we generated a RBM20 S639G mutation knock-in (KI) mouse model to validate the function of S639G mutation and examine the underlying mechanisms. KI mice exhibited severe DCM and premature death with a ~ 50% mortality in two months old homozygous (HM) mice. KI mice had enlarged atria and increased ANP and BNP biomarkers. The S639G mutation promoted RBM20 trafficking and ribonucleoprotein (RNP) granules in the sarcoplasm. RNA Seq data revealed differentially expressed and spliced genes were associated with arrhythmia, cardiomyopathy, and sudden death. KI mice also showed a reduction of diastolic stiffness and impaired contractility at both the left ventricular (LV) chamber and cardiomyocyte levels. Our results indicate that the RBM20 S639G mutation leads to RNP granules causing severe heart failure and early death and this finding strengthens the novel concept that RBM20 cardiomyopathy is a RNP granule disease. Graphical abstract: Unlabelled Image Highlights: An RBM20 mutation S639G leads to dilated cardiomyopathy and high mortality rate. Mutation results in RBM20 nucleocytoplasmic transport and protein condensates. Protein condensates caused by RBM20 mutation are a new causative mechanism of DCM.