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

Cecile Terrenoire, Kai Wang, Kelvin W. Chan Tung, Wendy K. Chung, Robert H. Pass, Jonathan T. Lu, Jyh Chang Jean, Amel Omari, Kevin J. Sampson, Darrell N. Kotton, Gordon Keller, Robert S. Kass

Research output: Contribution to journalArticle

108 Citations (Scopus)

Abstract

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 (INaL) 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 INaL such that increasing the pacing rate markedly reduces INaL 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.

Original languageEnglish (US)
Pages (from-to)61-72
Number of pages12
JournalJournal of General Physiology
Volume141
Issue number1
DOIs
StatePublished - Jan 2013

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Long QT Syndrome
Induced Pluripotent Stem Cells
Cardiac Myocytes
Cardiac Arrhythmias
Pharmaceutical Preparations
Pharmacology
Mexiletine
Biophysics
Mutation
Genomics
Drug Interactions
Ion Channels
Drug Therapy
Genes

ASJC Scopus subject areas

  • Physiology

Cite this

Terrenoire, C., Wang, K., Chan Tung, K. W., Chung, W. K., Pass, R. H., Lu, J. T., ... Kass, R. S. (2013). Induced pluripotent stem cells used to reveal drug actions in a long QT syndrome family with complex genetics. Journal of General Physiology, 141(1), 61-72. https://doi.org/10.1085/jgp.201210899

Induced pluripotent stem cells used to reveal drug actions in a long QT syndrome family with complex genetics. / Terrenoire, Cecile; Wang, Kai; Chan Tung, Kelvin W.; 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.

In: Journal of General Physiology, Vol. 141, No. 1, 01.2013, p. 61-72.

Research output: Contribution to journalArticle

Terrenoire, C, Wang, K, Chan Tung, KW, Chung, WK, Pass, RH, Lu, JT, Jean, JC, Omari, A, Sampson, KJ, Kotton, DN, Keller, G & Kass, RS 2013, 'Induced pluripotent stem cells used to reveal drug actions in a long QT syndrome family with complex genetics', Journal of General Physiology, vol. 141, no. 1, pp. 61-72. https://doi.org/10.1085/jgp.201210899
Terrenoire, Cecile ; Wang, Kai ; Chan Tung, Kelvin W. ; 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. / Induced pluripotent stem cells used to reveal drug actions in a long QT syndrome family with complex genetics. In: Journal of General Physiology. 2013 ; Vol. 141, No. 1. pp. 61-72.
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