ArticlePacing and clinical electrophysiology : PACE2011
A dual mechanism for I(Ks) current reduction by the pathogenic mutation KCNQ1-S277L.
Article in Pacing and clinical electrophysiology : PACE, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed, 16 citations in OpenAlex.
- Mutation location and IKs regulation in the arrhythmic risk of long QT syndrome type 1: the importance of the KCNQ1 S6 region.European heart journal · 2021Article
- Structures Illuminate Cardiac Ion Channel Functions in Health and in Long QT Syndrome.Frontiers in pharmacology · 2020Review
- Genetic testing in sudden unexpected natural death in the young: New York City Office of Chief Medical Examiner's experience and perspective.Forensic science, medicine, and pathology · 2019Article
- Article
- Computational approaches to understand cardiac electrophysiology and arrhythmias.American journal of physiology. Heart and circulatory physiology · 2012Review
- Potassium-channel mutations and cardiac arrhythmias--diagnosis and therapy.Nature reviews. Cardiology · 2012Review
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
Abstract
backgroundThe 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.
methodsThe KCNQ1-S277L mutation was analyzed via whole-cell patch clamp, confocal imaging, surface biotinylation assays, and computer modeling.
resultsHomomeric 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.
conclusionThe 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.
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