Isogenic models of hypertrophic cardiomyopathy unveil differential phenotypes and mechanism-driven therapeutics.

Journal of Molecular and Cellular Cardiology
Jamie R BhagwanChris Denning

Abstract

Hypertrophic cardiomyopathy (HCM) is a prevalent and complex cardiovascular condition. Despite being strongly associated with genetic alterations, wide variation of disease penetrance, expressivity and hallmarks of progression complicate treatment. We aimed to characterize different human isogenic cellular models of HCM bearing patient-relevant mutations to clarify genetic causation and disease mechanisms, hence facilitating the development of effective therapeutics. We directly compared the p.β-MHC-R453C and p.ACTC1-E99K HCM-associated mutations in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and their healthy isogenic counterparts, generated using CRISPR/Cas9 genome editing technology. By harnessing several state-of-the-art HCM phenotyping techniques, these mutations were investigated to identify similarities and differences in disease progression and hypertrophic signaling pathways, towards establishing potential targets for pharmacological treatment. CRISPR/Cas9 knock-in of the genetically-encoded calcium indicator R-GECO1.0 to the AAVS1 locus into these disease models resulted in calcium reporter lines. Confocal line scan analysis identified calcium transient arrhythmias and intracellular calcium ...Continue Reading

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Citations

Jul 29, 2020·Journal of Clinical Medicine·Parisa K KargaranDiogo Mosqueira
Aug 14, 2020·Methods and Protocols·Sara E BodbinDiogo Mosqueira
Feb 16, 2021·Frontiers in Cardiovascular Medicine·Parisa K KargaranTamas Kozicz
Mar 20, 2021·Cell Chemical Biology·Anna P HnatiukMark Mercola
Apr 4, 2021·Journal of Clinical Medicine·Ilaria My, Elisa Di Pasquale

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Methods Mentioned

BETA
biopsies
PCR
genotyping
PCR-genotyping
confocal microscopy
nuclear translocation
nuclear

Software Mentioned

GraphPad
CellOPTIQ®
pClamp

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