iPSC modeling of RBM20-deficient DCM identifies upregulation of RBM20 as a therapeutic strategy


  • F. Briganti
  • H. Sun
  • W. Wei
  • J. Wu
  • C. Zhu
  • M. Liss
  • I. Karakikes
  • S. Rego
  • A. Cipriano
  • M. Snyder
  • B. Meder
  • Z. Xu
  • G. Millat
  • M. Gotthardt
  • M. Mercola
  • L.M. Steinmetz


  • Cell Reports


  • Cell Rep 32 (10): 108117


  • Recent advances in induced pluripotent stem cell (iPSC) technology and directed differentiation of iPSCs into cardiomyocytes (iPSC-CMs) make it possible to model genetic heart disease in vitro. We apply CRISPR/Cas9 genome editing technology to introduce three RBM20 mutations in iPSCs and differentiate them into iPSC-CMs to establish an in vitro model of RBM20 mutant dilated cardiomyopathy (DCM). In iPSC-CMs harboring a known causal RBM20 variant, the splicing of RBM20 target genes, calcium handling, and contractility are impaired consistent with the disease manifestation in patients. A variant (Pro633Leu) identified by exome sequencing of patient genomes displays the same disease phenotypes, thus establishing this variant as disease causing. We find that all-trans retinoic acid upregulates RBM20 expression and reverts the splicing, calcium handling, and contractility defects in iPSC-CMs with different causal RBM20 mutations. These results suggest that pharmacological upregulation of RBM20 expression is a promising therapeutic strategy for DCM patients with a heterozygous mutation in RBM20.