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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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