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Dilated cardiomyopathy (DCM) is a leading cause of heart failure. In families with autosomal-dominant DCM, heterozygous missense mutations were identified in RNA-binding motif protein 20 ( RBM20 ), a spliceosome protein induced during early cardiogenesis. Dermal fibroblasts from two unrelated patients harboring an  RBM20  R636S missense mutation were reprogrammed to human induced pluripotent stem cells (hiPSCs) and differentiated to beating cardiomyocytes (CMs). Stage-specific transcriptome profiling identified differentially expressed genes ranging from angiogenesis regulator to embryonic heart transcription factor as initial molecular aberrations. Furthermore, gene expression analysis for  RBM20- dependent splice variants affected sarcomeric ( TTN  and  LDB3 ) and calcium (Ca 2+ ) handling ( CAMK2D  and  CACNA1C ) genes. Indeed,  RBM20  hiPSC-CMs exhibited increased sarcomeric length ( RBM20 : 1.747 ± 0.238 µm versus control: 1.404 ± 0.194 µm;  P  &lt; 0.0001) and decreased sarcomeric width ( RBM20 : 0.791 ± 0.609 µm versus control: 0.943 ± 0.166 µm;  P  &lt; 0.0001). Additionally, CMs showed defective Ca 2+  handling machinery with prolonged Ca 2+  levels in the cytoplasm as measured by greater area under the curve ( RBM20 : 814.718 ± 94.343 AU versus control: 206.941 ± 22.417 AU;  P  &lt; 0.05) and higher Ca 2+  spike amplitude ( RBM20 : 35.281 ± 4.060 AU versus control:18.484 ± 1.518 AU;  P  &lt; 0.05). β-adrenergic stress induced with 10 µ m  norepinephrine demonstrated increased susceptibility to sarcomeric disorganization ( RBM20 : 86 ± 10.5% versus control: 40 ± 7%;  P  &lt; 0.001). This study features the first hiPSC model of  RBM20  familial DCM. By monitoring human cardiac disease according to stage-specific cardiogenesis, this study demonstrates  RBM20  familial DCM is a developmental disorder initiated by molecular defects that pattern maladaptive cellular mechanisms of pathological cardiac remodeling. Indeed, hiPSC-CMs recapitulate  RBM20  familial DCM phenotype in a dish and establish a tool to dissect disease-relevant defects in  RBM20  splicing as a global regulator of heart function.

Modeling structural and functional deficiencies of RBM20 familial dilated cardiomyopathy using human induced pluripotent stem cells