RBM20 mutations result in cardiac remodelling and pathogenesis in mice

Genetic studies show that mutations in a gene named as RNA binding motif 20 (RBM20) are associated with dilated cardiomyopathy (DCM). We selected two mutations (S637A and S639G) located in arginine/serine-rich (RS) domain of RNA binding motif 20 (RBM20) and generated two knock-in mouse models (Rbm20S637A and Rbm20S639G) respectively. The heterozygous (HT) and homozygous (HM) in both mouse lines displayed DCM phenotype with enlarged left ventricular (LV) chamber, thinner ventricular walls and reduced ejection fraction. We also observed higher mortality rate in both HM mice, ~50% in Rbm20S639G and ~34% in Rbm20S637A at an early age (<100days). Differentially expressed and spliced genes from RNA-seq data were involved in arrhythmia, cardiomyopathy, and sudden death based on Human Phenotype Ontology enrichment analysis (FDR≤0.05) in both mouse lines. Immunofluorescent analysis in tissues and single cardiomyocytes respectively showed both mutations promote RBM20 nucleocytoplasmic trafficking and protein condensates, suggesting they are gain-of-function mutations, leading to high mortality rate at younger age. Together, we reported a new mechanism by which cardiac genetic mutations causes protein trafficking and RNA-protein aggregation in cardiac remodelling. Study the underlying mechanisms of two Rbm20 mutations in cardiac remodeling in mice.