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

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  • 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
  • Chris Denning

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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.


Original languageEnglish
Pages (from-to)1226-1243
Number of pages18
JournalStem Cell Reports
Issue number5
Early online date1 Nov 2018
Publication statusPublished - 13 Nov 2018

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