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Dilated cardiomyopathy (DCM) due to mutations in  RBM20 , a gene encoding an RNA-binding protein, is associated with high familial penetrance, risk of progressive heart failure and sudden death. Although genetic investigations and physiological models have established the linkage of  RBM20  with early-onset DCM, the underlying basis of cellular and molecular dysfunction is undetermined. Modeling human genetics using a high-throughput pluripotent stem cell platform was herein designed to pinpoint the initial transcriptome dysfunction and mechanistic corruption in disease pathogenesis. Tnnt2-pGreenZeo pluripotent stem cells were engineered to knockdown  Rbm20  (shRbm20) to determine the cardiac-pathogenic phenotype during cardiac differentiation. Intracellular Ca 2+  transients revealed  Rbm20 -dependent alteration in Ca 2+  handling, coinciding with known pathological splice variants of  Titin  and  Camk2d  genes by Day 24 of cardiogenesis. Ultrastructural analysis demonstrated elongated and thinner sarcomeres in the absence of  Rbm20  that is consistent with human cardiac biopsy samples .  Furthermore,  Rbm20 -depleted transcriptional profiling at Day 12 identified  Rbm20 -dependent dysregulation with 76% of differentially expressed genes linked to known cardiac pathology ranging from primordial  Nkx2.5  to mature cardiac  Tnnt2  as the initial molecular aberrations. Notably, downstream consequences of  Rbm20 -depletion at Day 24 of differentiation demonstrated significant dysregulation of extracellular matrix components such as the anomalous overexpression of the  Vtn  gene. By using the pluripotent stem cell platform to model human cardiac disease according to a stage-specific cardiogenic roadmap, we established a new paradigm of familial DCM pathogenesis as a developmental disorder that is patterned during early cardiogenesis and propagated with cellular mechanisms of pathological cardiac remodeling.

human molecular genetics

Rbm20-deficient cardiogenesis reveals early disruption of RNA processing and sarcomere remodeling establishing a developmental etiology for dilated cardiomyopathy