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

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

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., Sun, H., Wei, W., Wu, J., Zhu, C., Liss, M., Karakikes, I., Rego, S., Cipriano, A., Snyder, M., Meder, B., Xu, Z., Millat, G., Gotthardt, M., 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
ISSN:	2211-1247
Publisher:	Cell Press / Elsevier
Volume:	32
Number:	10
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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