ArticleThe Journal of general physiology2010
Mechanistic basis for LQT1 caused by S3 mutations in the KCNQ1 subunit of IKs.
Article in The Journal of general physiology, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 31 citations in OpenAlex.
- Long QT Syndrome Type 5 With Coexisting KCNE1 and RYR2 Variants: A Diagnostic Ambiguity.Clinical case reports · 2026Article
- Genetic Background and Clinical Phenotype in an Italian Cohort with Inherited Arrhythmia Syndromes and Arrhythmogenic Cardiomyopathy (ACM): A Whole-Exome Sequencing Study.International journal of molecular sciences · 2025Article
- From genes to clinical management: A comprehensive review of long QT syndrome pathogenesis and treatment.Heart rhythm O2 · 2024Review
- Screening for Rare Coding Variants That Associate With the QTc Interval in Iceland.Journal of the American Heart Association · 2023Article
- The Pathological Mechanisms of Hearing Loss Caused byBiomedicines · 2022Review
- Long-QT founder variant T309I-Kv7.1 with dominant negative pattern may predispose delayed afterdepolarizations under β-adrenergic stimulation.Scientific reports · 2021Article
- Polyunsaturated fatty acids produce a range of activators for heterogeneous IKs channel dysfunction.The Journal of general physiology · 2020Article
- The IBiophysical journal · 2018Article
- High-Throughput Functional Evaluation of KCNQ1 Decrypts Variants of Unknown Significance.Circulation. Genomic and precision medicine · 2018Article
- Modeling the Hidden Pathways of IKs Channel Activation.Biophysical journal · 2018Article
- Single channel kinetic analysis of the cAMP effect on IChannels (Austin, Tex.) · 2018Article
- cAMP-dependent regulation ofThe Journal of general physiology · 2017Article
- Molecular Pathophysiology of Congenital Long QT Syndrome.Physiological reviews · 2017Review
- Aggregate penetrance of genomic variants for actionable disorders in European and African Americans.Science translational medicine · 2016Article
- Article
- Cardiac Delayed Rectifier Potassium Channels in Health and Disease.Cardiac electrophysiology clinics · 2016Review
- Understanding the microscopic mechanisms for LQT1 needs a global view of the I(Ks) channel.Heart rhythm · 2015Article
- Single-channel basis for the slow activation of the repolarizing cardiac potassium current, I(Ks).Proceedings of the National Academy of Sciences of the United States of America · 2013Article
- Working model for the structural basis for KCNE1 modulation of the KCNQ1 potassium channel.Current opinion in structural biology · 2011Review
- Novel mutations of KCNQ1 in Long QT syndrome.Indian heart journalReview
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Authors and funding
10 authors at 3 institutions in 2 countries.
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Abstract
Long QT interval syndrome (LQTS) type 1 (LQT1) has been reported to arise from mutations in the S3 domain of KCNQ1, but none of the seven S3 mutations in the literature have been characterized with respect to trafficking or biophysical deficiencies. Surface channel expression was studied using a proteinase K assay for KCNQ1 D202H/N, I204F/M, V205M, S209F, and V215M coexpressed with KCNE1 in mammalian cells. In each case, the majority of synthesized channel was found at the surface, but mutant I(Ks) current density at +100 mV was reduced significantly for S209F, which showed approximately 75% reduction over wild type (WT). All mutants except S209F showed positively shifted V(1/2)'s of activation and slowed channel activation compared with WT (V(1/2) = +17.7 +/- 2.4 mV and tau(activation) of 729 ms at +20 mV; n = 18). Deactivation was also accelerated in all mutants versus WT (126 +/- 8 ms at -50 mV; n = 27), and these changes led to marked loss of repolarizing currents during action potential clamps at 2 and 4 Hz, except again S209F. KCNQ1 models localize these naturally occurring S3 mutants to the surface of the helices facing the other voltage sensor transmembrane domains and highlight inter-residue interactions involved in activation gating. V207M, currently classified as a polymorphism and facing lipid in the model, was indistinguishable from WT I(Ks). We conclude that S3 mutants of KCNQ1 cause LQTS predominantly through biophysical effects on the gating of I(Ks), but some mutants also show protein stability/trafficking defects, which explains why the kinetic gain-of-function mutation S209F causes LQT1.
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