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 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.
Original language | English (US) |
---|---|
Pages (from-to) | 1652-1664 |
Number of pages | 13 |
Journal | PACE - Pacing and Clinical Electrophysiology |
Volume | 34 |
Issue number | 12 |
DOIs | |
State | Published - Dec 2011 |
Keywords
- Disease mechanism
- Genetic phenotype
- I
- KCNQ1
- Sudden death
- long QT syndrome
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine