Isogenic Pairs of hiPSC-CMs with Hypertrophic Cardiomyopathy/LVNC-Associated ACTC1 E99K Mutation Unveil Differential Functional Deficits

Smith, James G.w., Owen, Thomas, Bhagwan, Jamie R., Mosqueira, Diogo, Scott, Elizabeth, Mannhardt, Ingra, Patel, Asha, Barriales-Villa, Roberto, Monserrat, Lorenzo, Hansen, Arne, Eschenhagen, Thomas, Harding, Sian E., Marston, Steve and Denning, Chris (2018) Isogenic Pairs of hiPSC-CMs with Hypertrophic Cardiomyopathy/LVNC-Associated ACTC1 E99K Mutation Unveil Differential Functional Deficits. Stem Cell Reports, 11 (5). pp. 1226-1243. ISSN 2213-6711

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Abstract

Hypertrophic cardiomyopathy (HCM) is a primary disorder of contractility in heart muscle. To gain mechanistic insight and guide pharmacological rescue, this study models HCM using isogenic pairs of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) carrying the E99K-ACTC1 cardiac actin mutation. In both 3D engineered heart tissues and 2D monolayers, arrhythmogenesis was evident in all E99K-ACTC1 hiPSC-CMs. Aberrant phenotypes were most common in hiPSC-CMs produced from the heterozygote father. Unexpectedly, pathological phenotypes were less evident in E99K-expressing hiPSC-CMs from the two sons. Mechanistic insight from Ca2+ handling expression studies prompted pharmacological rescue experiments, wherein dual dantroline/ranolazine treatment was most effective. Our data are consistent with E99K mutant protein being a central cause of HCM but the three-way interaction between the primary genetic lesion, background (epi)genetics, and donor patient age may influence the pathogenic phenotype. This illustrates the value of isogenic hiPSC-CMs in genotype-phenotype correlations.

Item Type: Article
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: LivePure Connector
Date Deposited: 08 Jan 2019 16:30
Last Modified: 19 Oct 2020 23:47
URI: https://ueaeprints.uea.ac.uk/id/eprint/69494
DOI: 10.1016/j.stemcr.2018.10.006

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