{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,20]],"date-time":"2025-09-20T21:08:13Z","timestamp":1758402493708,"version":"3.38.0"},"reference-count":42,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2011,9,2]],"date-time":"2011-09-02T00:00:00Z","timestamp":1314921600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pacing Clinical Electrophis"],"published-print":{"date-parts":[[2011,12]]},"abstract":"<jats:p><jats:bold><jats:italic>Background:<\/jats:italic><\/jats:bold>\u2002<jats:italic>The hereditary long QT syndrome is characterized by prolonged ventricular repolarization that can be caused by mutations to the KCNQ1 gene, which encodes the \u03b1 subunits of the cardiac potassium channel complex that carries the I<jats:sub>Ks<\/jats:sub>current (the \u03b2 subunits are encoded by KCNE1). In this study, we characterized a deleterious variant, KCNQ1\u2010S277L, found in a patient who presented with sudden cardiac death in the presence of cocaine use.<\/jats:italic><\/jats:p><jats:p><jats:bold><jats:italic>Methods:<\/jats:italic><\/jats:bold>\u2002<jats:italic>The KCNQ1\u2010S277L mutation was analyzed via whole\u2010cell patch clamp, confocal imaging, surface biotinylation assays, and computer modeling.<\/jats:italic><\/jats:p><jats:p><jats:bold><jats:italic>Results:<\/jats:italic><\/jats:bold>\u2002<jats:italic>Homomeric mutant KCNQ1\u2010S277L channels were unable to carry current, either alone or with KCNE1. When co\u2010expressed in a 50\/50 ratio with WT KCNQ1, current density was reduced in a dominant\u2010negative manner, with the residual current predominantly wild type. There was no change in the activation rate and minimal changes to voltage\u2010dependent activation for both KCNQ1 current and I<jats:sub>Ks<\/jats:sub>current. Immunofluorescence confocal imaging revealed reduced surface expression of mutant KCNQ1\u2010S277L, which was biochemically confirmed by surface biotinylation showing a 44% decrease in mutant surface expression. Expression of KCNQ1\u2010S277L with human ether\u2010a\u2010go\u2010go\u2010related gene (HERG) did not significantly affect HERG protein or current density compared to KCNQ1\u2010WT co\u2010expression.<\/jats:italic><\/jats:p><jats:p><jats:bold><jats:italic>Conclusion:<\/jats:italic><\/jats:bold>\u2002<jats:italic>The KCNQ1\u2010S277L mutation causes biophysical defects that result in dominant\u2010negative reduction in KCNQ1 and I<jats:sub>Ks<\/jats:sub>current density, and a trafficking defect that results in reduced surface expression, both without affecting HERG\/I<jats:sub>Kr<\/jats:sub>. KCNQ1\u2010S277L mutation in the proband resulted in defective channels that compromised repolarization reserve, thereby enhancing the arrhythmic susceptibility to pharmacological blockage of I<jats:sub>Kr<\/jats:sub>current. (PACE 2011; 34:1652\u20131664)<\/jats:italic><\/jats:p>","DOI":"10.1111\/j.1540-8159.2011.03190.x","type":"journal-article","created":{"date-parts":[[2011,9,2]],"date-time":"2011-09-02T15:58:21Z","timestamp":1314979101000},"page":"1652-1664","source":"Crossref","is-referenced-by-count":15,"title":["A Dual Mechanism for I<sub>Ks<\/sub>Current Reduction by the Pathogenic Mutation KCNQ1\u2010S277L"],"prefix":"10.1111","volume":"34","author":[{"given":"JERRI","family":"CHEN","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"MICHAEL","family":"WEBER","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"SUNG","family":"YON UM","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"CHRISTINE A.","family":"WALSH","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"YINGYING","family":"TANG","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"THOMAS V.","family":"MCDONALD","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2011,9,2]]},"reference":[{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.103.054569"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(00)00302-3"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/384078a0"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1038\/384080a0"},{"key":"e_1_2_6_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80728-X"},{"key":"e_1_2_6_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/40882"},{"key":"e_1_2_6_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2008.01.006"},{"key":"e_1_2_6_9_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.103.1.89"},{"key":"e_1_2_6_10_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.105.570200"},{"key":"e_1_2_6_11_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2148-8-188"},{"key":"e_1_2_6_12_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.9085"},{"key":"e_1_2_6_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2005.01.020"},{"key":"e_1_2_6_14_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00275.2003"},{"key":"e_1_2_6_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2004.06.001"},{"key":"e_1_2_6_16_2","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1124\/mol.109.062216","article-title":"Post\u2010transcriptional control of human ether\u2010a\u2010go\u2010go\u2010related gene potassium channel protein by alpha\u2010adrenergic receptor stimulation","volume":"78","author":"Chen J","journal-title":"Mol Pharmacol"},{"key":"e_1_2_6_17_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00656997"},{"key":"e_1_2_6_18_2","first-page":"36","article-title":"Image processing with image","volume":"11","author":"Abramoff MD","year":"2004","journal-title":"J Biophotonics Int"},{"key":"e_1_2_6_19_2","doi-asserted-by":"publisher","DOI":"10.1021\/bi701597s"},{"key":"e_1_2_6_20_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/18.12.1701"},{"key":"e_1_2_6_21_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.87.6.1866"},{"key":"e_1_2_6_22_2","first-page":"2246","article-title":"Mechanisms of cardiac arrhythmias and sudden death in transgenic rabbits with long QT syndrome","volume":"118","author":"Brunner M","year":"2008","journal-title":"J Clin Invest"},{"key":"e_1_2_6_23_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M309087200"},{"key":"e_1_2_6_24_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00479.2009"},{"key":"e_1_2_6_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2011.01.008"},{"key":"e_1_2_6_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2005.04.036"},{"key":"e_1_2_6_27_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/16.17.5472"},{"key":"e_1_2_6_28_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1540-8167.1999.tb00262.x"},{"key":"e_1_2_6_29_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.2000.279.6.H3003"},{"key":"e_1_2_6_30_2","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.39.9.681"},{"key":"e_1_2_6_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2009.01.051"},{"key":"e_1_2_6_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.yjmcc.2007.04.012"},{"key":"e_1_2_6_33_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.105.572453"},{"key":"e_1_2_6_34_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1540-8159.1998.tb00148.x"},{"key":"e_1_2_6_35_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.105.550111"},{"key":"e_1_2_6_36_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2125.2008.03327.x"},{"key":"e_1_2_6_37_2","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.102.038240"},{"key":"e_1_2_6_38_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmcc.1996.0062"},{"key":"e_1_2_6_39_2","doi-asserted-by":"publisher","DOI":"10.1124\/mol.59.5.1069"},{"key":"e_1_2_6_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0379-0738(99)00006-7"},{"key":"e_1_2_6_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(01)00458-8"},{"key":"e_1_2_6_42_2","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/S0022-3565(24)29321-6","article-title":"Effects of cocaine and its major metabolites on the HERG\u2010encoded potassium channel","volume":"299","author":"Ferreira S","year":"2001","journal-title":"J Pharmacol Exp Therapeutics"},{"key":"e_1_2_6_43_2","unstructured":"[please add the details of this article's companion article (Krishnan Y. et al. PACE\u201011\u20100278.R2) when available]."}],"container-title":["Pacing and Clinical Electrophysiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fj.1540-8159.2011.03190.x","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/j.1540-8159.2011.03190.x","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,9]],"date-time":"2025-03-09T18:17:51Z","timestamp":1741544271000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/j.1540-8159.2011.03190.x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,9,2]]},"references-count":42,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2011,12]]}},"alternative-id":["10.1111\/j.1540-8159.2011.03190.x"],"URL":"https:\/\/doi.org\/10.1111\/j.1540-8159.2011.03190.x","archive":["Portico"],"relation":{},"ISSN":["0147-8389","1540-8159"],"issn-type":[{"type":"print","value":"0147-8389"},{"type":"electronic","value":"1540-8159"}],"subject":[],"published":{"date-parts":[[2011,9,2]]}}}