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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; Denning, Chris


James G.W. Smith

Thomas Owen

Jamie R. Bhagwan

Diogo Mosqueira

Elizabeth Scott

Ingra Mannhardt

Asha Patel

Roberto Barriales-Villa

Lorenzo Monserrat

Arne Hansen

Thomas Eschenhagen

Sian E. Harding

Steve Marston

Professor of Stem Cell Biology


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 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.


Smith, J. G., Owen, T., Bhagwan, J. R., Mosqueira, D., Scott, E., Mannhardt, I., …Denning, C. (2018). Isogenic pairs of hiPSC-CMs with hypertrophic cardiomyopathy/LVNC-associated ACTC1 E99K mutation unveil differential functional deficits. Stem Cell Reports, 11(5), 1226-1243.

Journal Article Type Article
Acceptance Date Oct 5, 2018
Online Publication Date Nov 1, 2018
Publication Date Nov 13, 2018
Deposit Date Oct 8, 2018
Publicly Available Date Nov 2, 2018
Journal Stem Cell Reports
Electronic ISSN 2213-6711
Publisher Cell Press
Peer Reviewed Peer Reviewed
Volume 11
Issue 5
Pages 1226-1243
Public URL
Publisher URL
Additional Information This article is maintained by: Elsevier; Article Title: Isogenic Pairs of hiPSC-CMs with Hypertrophic Cardiomyopathy/LVNC-Associated ACTC1 E99K Mutation Unveil Differential Functional Deficits; Journal Title: Stem Cell Reports; CrossRef DOI link to publisher maintained version:; Content Type: article; Copyright: © 2018 The Author(s).


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