{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T05:47:09Z","timestamp":1791352029082,"version":"4.3.1"},"reference-count":43,"publisher":"Rockefeller University Press","issue":"1","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2013,1,1]]},"abstract":"<jats:p>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\u2019s iPSC-CMs, correlate with improved management of arrhythmias in the patient and provide support for this approach in developing patient-specific clinical regimens.<\/jats:p>","DOI":"10.1085\/jgp.201210899","type":"journal-article","created":{"date-parts":[[2012,12,31]],"date-time":"2012-12-31T15:48:01Z","timestamp":1356968881000},"page":"61-72","update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":177,"title":["Induced pluripotent stem cells used to reveal drug actions in a long QT syndrome family with complex genetics"],"prefix":"10.1085","volume":"141","author":[{"given":"Cecile","family":"Terrenoire","sequence":"first","affiliation":[{"name":"Department of Pharmacology 1 , 2 , and 3"},{"name":"Department of Medicine 1 , 2 , and 3"},{"name":"Department of Pediatrics, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY 10032 1 , 2 , and 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology 1 , 2 , and 3"},{"name":"Department of Medicine 1 , 2 , and 3"},{"name":"Department of Pediatrics, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY 10032 1 , 2 , and 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelvin W.","family":"Chan Tung","sequence":"additional","affiliation":[{"name":"McEwen Centre for Regenerative Medicine, University Health Network, Toronto, Ontario M5G 1L7, Canada 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendy K.","family":"Chung","sequence":"additional","affiliation":[{"name":"Department of Pharmacology 1 , 2 , and 3"},{"name":"Department of Medicine 1 , 2 , and 3"},{"name":"Department of Pediatrics, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY 10032 1 , 2 , and 3"},{"name":"Department of Pharmacology 1 , 2 , and 3"},{"name":"Department of Medicine 1 , 2 , and 3"},{"name":"Department of Pediatrics, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY 10032 1 , 2 , and 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert H.","family":"Pass","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Albert Einstein College of Medicine, The Children\u2019s Hospital at Montefiore, Bronx, NY 10467 6"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan T.","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology 1 , 2 , and 3"},{"name":"Department of Medicine 1 , 2 , and 3"},{"name":"Department of Pediatrics, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY 10032 1 , 2 , and 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jyh-Chang","family":"Jean","sequence":"additional","affiliation":[{"name":"Center for Regenerative Medicine, Boston University and Boston Medical Center, Boston, MA 02118 5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amel","family":"Omari","sequence":"additional","affiliation":[{"name":"Center for Regenerative Medicine, Boston University and Boston Medical Center, Boston, MA 02118 5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin J.","family":"Sampson","sequence":"additional","affiliation":[{"name":"Department of Pharmacology 1 , 2 , and 3"},{"name":"Department of Medicine 1 , 2 , and 3"},{"name":"Department of Pediatrics, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY 10032 1 , 2 , and 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darrell N.","family":"Kotton","sequence":"additional","affiliation":[{"name":"Center for Regenerative Medicine, Boston University and Boston Medical Center, Boston, MA 02118 5"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gordon","family":"Keller","sequence":"additional","affiliation":[{"name":"McEwen Centre for Regenerative Medicine, University Health Network, Toronto, Ontario M5G 1L7, Canada 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert S.","family":"Kass","sequence":"additional","affiliation":[{"name":"Department of Pharmacology 1 , 2 , and 3"},{"name":"Department of Medicine 1 , 2 , and 3"},{"name":"Department of Pediatrics, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY 10032 1 , 2 , and 3"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2012,12,31]]},"reference":[{"key":"2023072622433565900_bib1","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1161\/01.RES.79.1.103","article-title":"Lidocaine block of LQT-3 mutant human Na+ channels","volume":"79","author":"An","year":"1996","journal-title":"Circ. 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