Induced pluripotent stem cells used to reveal drug actions in a long QT syndrome family with complex genetics

• Published in: The Journal of general physiology 2013-01, Vol.141 (1), p.61-72
• Main Authors: Terrenoire, Cecile, Wang, Kai, Tung, Kelvin W Chan, Chung, Wendy K, Pass, Robert H, Lu, Jonathan T, Jean, Jyh-Chang, Omari, Amel, Sampson, Kevin J, Kotton, Darrell N, Keller, Gordon, Kass, Robert S
• Format: Article
• Language: English
• Subjects: Anti-Arrhythmia Agents - pharmacology; Anti-Arrhythmia Agents - therapeutic use; Biophysical Phenomena; Cardiomyocytes; Cell Communication; Cells, Cultured; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels - genetics; Flecainide - pharmacology; Flecainide - therapeutic use; Genomics; Humans; Infant, Newborn; Long QT Syndrome - drug therapy; Long QT Syndrome - genetics; Long QT Syndrome - pathology; Male; Mexiletine - pharmacology; Mexiletine - therapeutic use; Mutation; Mutation - genetics; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - pathology; NAV1.5 Voltage-Gated Sodium Channel - genetics; Pharmacogenetics; Pluripotent Stem Cells - cytology; Pluripotent Stem Cells - drug effects; Pluripotent Stem Cells - physiology; Polymorphism; Sodium Channels - drug effects; Sodium Channels - physiology; Stem cells; Treatment Outcome
• ISSN: 0022-1295; 1540-7748
• DOI: 10.1085/jgp.201210899

Understanding the basis for differential responses to drug therapies remains a challenge despite advances in genetics and genomics. Induced pluripotent stem cells (iPSCs) offer an unprecedented opportunity to investigate the pharmacology of disease processes in therapeutically and genetically relevant primary cell types in vitro and to interweave clinical and basic molecular data. We report here the derivation of iPSCs from a long QT syndrome patient with complex genetics. The proband was found to have a de novo SCN5A LQT-3 mutation (F1473C) and a polymorphism (K897T) in KCNH2, the gene for LQT-2. Analysis of the biophysics and molecular pharmacology of ion channels expressed in cardiomyocytes (CMs) differentiated from these iPSCs (iPSC-CMs) demonstrates a primary LQT-3 (Na(+) channel) defect responsible for the arrhythmias not influenced by the KCNH2 polymorphism. The F1473C mutation occurs in the channel inactivation gate and enhances late Na(+) channel current (I(NaL)) that is carried by channels that fail to inactivate completely and conduct increased inward current during prolonged depolarization, resulting in delayed repolarization, a prolonged QT interval, and increased risk of fatal arrhythmia. We find a very pronounced rate dependence of I(NaL) such that increasing the pacing rate markedly reduces I(NaL) and, in addition, increases its inhibition by the Na(+) channel blocker mexiletine. These rate-dependent properties and drug interactions, unique to the proband's iPSC-CMs, correlate with improved management of arrhythmias in the patient and provide support for this approach in developing patient-specific clinical regimens.