iPSC modeling of RBM20-deficient DCM identifies upregulation of RBM20 as a therapeutic strategy
Authors
- 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
Journal
- Cell Reports
Citation
- Cell Rep 32 (10): 108117
Abstract
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.