ArticleEuropean heart journal2021
Mutation location and IKs regulation in the arrhythmic risk of long QT syndrome type 1: the importance of the KCNQ1 S6 region.
Article in European heart journal, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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28 citing papers in PubMed, 55 citations in OpenAlex.
- Machine learning-guided risk stratification for long QT syndrome genetic variants with hiPSC-derived cardiomyocytes.Cardiovascular research · 2026Article
- C-terminal long-QT type 1 R562S-Kv7.1 variant, the first variant in helix C impairing β-adrenergic response of the slow delayed rectifier K+ channel.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2026Article
- Nanomachines Based on Inner Ultrasonic Multiple Scattering for Ameliorating Renal Function.Advanced materials (Deerfield Beach, Fla.) · 2026Article
- A Novel A-Kinase-Anchoring Protein 9 Variant in Premature Coronary Artery Disease: A Case Series.Molecular genetics & genomic medicine · 2026Article
- Long QT syndrome type 1: clinical and functional characterization of KCNQ1 variant c.1111G > C.BMC cardiovascular disorders · 2025Article
- Spectrum of genetic variants detected in children tested for long QT syndrome.BMC cardiovascular disorders · 2025Article
- Uncovering possible silent acquired long QT syndrome using exercise stress testing in long-term pediatric acute lymphoblastic leukemia survivors.International journal of cancer · 2025Article
- Ion permeation through a narrow cavity constriction in KCNQ1 channels: Mechanism and implications for pathogenic variants.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Evaluation of the Potential Targets of Shenxian-Shengmai Oral Liquid in Treating Sick Sinus Syndrome Based on Network Pharmacology and Molecular Docking.Food science & nutrition · 2024Article
- The fully activated open state of KCNQ1 controls the cardiac "fight-or-flight" response.PNAS nexus · 2024Article
- Targeting the ICirculation research · 2024Article
- Genetic characterization of KCNQ1 variants improves risk stratification in type 1 long QT syndrome patients.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2024Article
- Article
- Enhancing the interpretation of genetic observations in KCNQ1 in unselected populations: relevance to secondary findings.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2023Article
- Effects of cohort, genotype, variant, and maternal β-blocker treatment on foetal heart rate predictors of inherited long QT syndrome.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2023Article
- Estimating the probability of early afterdepolarizations and predicting arrhythmic risk associated with long QT syndrome type 1 mutations.Biophysical journal · 2023Article
- From gene-discovery to gene-tailored clinical management: 25 years of research in channelopathies and cardiomyopathies.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2023Article
- Continuous Bayesian variant interpretation accounts for incomplete penetrance among Mendelian cardiac channelopathies.Genetics in medicine : official journal of the American College of Medical Genetics · 2023Article
- Genome-wide associated variants of subclinical atherosclerosis among young people with HIV and gene-environment interactions.Journal of translational medicine · 2022Article
- Genetics of congenital arrhythmia syndromes: the challenge of variant interpretation.Current opinion in genetics & development · 2022Review
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Authors and funding
16 authors at 7 institutions in 7 countries.
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No grant is acknowledged in the PubMed record.
Abstract
aimsMutation type, location, dominant-negative IKs reduction, and possibly loss of cyclic adenosine monophosphate (cAMP)-dependent IKs stimulation via protein kinase A (PKA) influence the clinical severity of long QT syndrome type 1 (LQT1). Given the malignancy of KCNQ1-p.A341V, we assessed whether mutations neighbouring p.A341V in the S6 channel segment could also increase arrhythmic risk. METHODS AND
resultsClinical and genetic data were obtained from 1316 LQT1 patients [450 families, 166 unique KCNQ1 mutations, including 277 p.A341V-positive subjects, 139 patients with p.A341-neighbouring mutations (91 missense, 48 non-missense), and 900 other LQT1 subjects]. A first cardiac event represented the primary endpoint. S6 segment missense variant characteristics, particularly cAMP stimulation responses, were analysed by cellular electrophysiology. p.A341-neighbouring mutation carriers had a QTc shorter than p.A341V carriers (477 ± 33 vs. 490 ± 44 ms) but longer than the remaining LQT1 patient population (467 ± 41 ms) (P < 0.05 for both). Similarly, the frequency of symptomatic subjects in the p.A341-neighbouring subgroup was intermediate between the other two groups (43% vs. 73% vs. 20%; P < 0.001). These differences in clinical severity can be explained, for p.A341V vs. p.A341-neighbouring mutations, by the p.A341V-specific impairment of IKs regulation. The differences between the p.A341-neighbouring subgroup and the rest of LQT1 mutations may be explained by the functional importance of the S6 segment for channel activation.
conclusionKCNQ1 S6 segment mutations surrounding p.A341 increase arrhythmic risk. p.A341V-specific loss of PKA-dependent IKs enhancement correlates with its phenotypic severity. Cellular studies providing further insights into IKs-channel regulation and knowledge of structure-function relationships could improve risk stratification. These findings impact on clinical management.
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