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

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Item Type:Article
Title:iPSC modeling of RBM20-deficient DCM identifies upregulation of RBM20 as a therapeutic strategy
Creators Name:Briganti, F. and Sun, H. and Wei, W. and Wu, J. and Zhu, C. and Liss, M. and Karakikes, I. and Rego, S. and Cipriano, A. and Snyder, M. and Meder, B. and Xu, Z. and Millat, G. and Gotthardt, M. and Mercola, M. and Steinmetz, L.M.
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.
Keywords:DCM, RBM20, Alternative Splicing, Precision Medicine, iPSC, Cardiomyocytes, Disease Modeling, Genome Editing
Source:Cell Reports
Publisher:Cell Press / Elsevier
Page Range:108117
Date:8 September 2020
Official Publication:https://doi.org/10.1016/j.celrep.2020.108117
PubMed:View item in PubMed

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