Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Stem cell reports, 2018-11, Vol.11 (5), p.1226-1243

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2018

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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. •Arrhythmia was a hallmark phenotype in E99K hiPSC-CMs, provoked by altered [Ca2+]•Monoallelic expression of E99K cardiac actin affects only half the cell population•Severe phenotypes in father's E99K hiPSC-CMs suggest influence of age & epigenetics•Mechanistic insight facilitated drug rescue with combined dantroline/ranolazine In this article Smith, Denning and colleagues show that the E99K-ACTC1 cardiac actin mutation is a central cause of HCM, but the three-way interaction between the primary genetic lesion, background genetics, and donor patient age may influence the pathogenic phenotype. Pharmacological rescue experiments demonstrated dual dantroline/ranolazine to be an effective treatment.