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- W1550019339 endingPage "1664" @default.
- W1550019339 startingPage "1652" @default.
- W1550019339 abstract "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 IKs 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 IKs 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 IKs current density, and a trafficking defect that results in reduced surface expression, both without affecting HERG/IKr. KCNQ1-S277L mutation in the proband resulted in defective channels that compromised repolarization reserve, thereby enhancing the arrhythmic susceptibility to pharmacological blockage of IKr current. (PACE 2011; 34:1652–1664)" @default.
- W1550019339 created "2016-06-24" @default.
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- W1550019339 date "2011-09-02" @default.
- W1550019339 modified "2023-10-01" @default.
- W1550019339 title "A Dual Mechanism for IKs Current Reduction by the Pathogenic Mutation KCNQ1-S277L" @default.
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- W1550019339 doi "https://doi.org/10.1111/j.1540-8159.2011.03190.x" @default.
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