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A Dual Mechanism for I Ks Current Reduction by the Pathogenic Mutation KCNQ1‐S277L
Author(s) -
CHEN JERRI,
WEBER MICHAEL,
YON UM SUNG,
WALSH CHRISTINE A.,
TANG YINGYING,
MCDONALD THOMAS V.
Publication year - 2011
Publication title -
pacing and clinical electrophysiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.686
H-Index - 101
eISSN - 1540-8159
pISSN - 0147-8389
DOI - 10.1111/j.1540-8159.2011.03190.x
Subject(s) - herg , mutation , mutant , patch clamp , potassium channel , long qt syndrome , microbiology and biotechnology , medicine , genetics , gene , electrophysiology , biology , qt interval
Background: The hereditary long QT syndrome is characterized by prolonged ventricular repolarization that can be caused by mutations to the KCNQ1 gene, which encodes the α subunits of the cardiac potassium channel complex that carries the I Ks current (the β subunits are encoded by KCNE1). In this study, we characterized a deleterious variant, KCNQ1‐S277L, found in a patient who presented with sudden cardiac death in the presence of cocaine use.Methods: The KCNQ1‐S277L mutation was analyzed via whole‐cell patch clamp, confocal imaging, surface biotinylation assays, and computer modeling.Results: Homomeric mutant KCNQ1‐S277L channels were unable to carry current, either alone or with KCNE1. When co‐expressed in a 50/50 ratio with WT KCNQ1, current density was reduced in a dominant‐negative manner, with the residual current predominantly wild type. There was no change in the activation rate and minimal changes to voltage‐dependent activation for both KCNQ1 current and I Ks current. Immunofluorescence confocal imaging revealed reduced surface expression of mutant KCNQ1‐S277L, which was biochemically confirmed by surface biotinylation showing a 44% decrease in mutant surface expression. Expression of KCNQ1‐S277L with human ether‐a‐go‐go‐related gene (HERG) did not significantly affect HERG protein or current density compared to KCNQ1‐WT co‐expression.Conclusion: The KCNQ1‐S277L mutation causes biophysical defects that result in dominant‐negative reduction in KCNQ1 and I Ks current density, and a trafficking defect that results in reduced surface expression, both without affecting HERG/I Kr . KCNQ1‐S277L mutation in the proband resulted in defective channels that compromised repolarization reserve, thereby enhancing the arrhythmic susceptibility to pharmacological blockage of I Kr current. (PACE 2011; 34:1652–1664)