ArticleHeart rhythm2012
Molecular genetic and functional association of Brugada and early repolarization syndromes with S422L missense mutation in KCNJ8.
Article in Heart rhythm, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 77 papers, 1 of them a synthesis that pooled it.
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Who cites it
77 citing papers in PubMed, 1 synthesis or guideline pooled it, 169 citations in OpenAlex.
- KCND3 potassium channel gene variant confers susceptibility to electrocardiographic early repolarization pattern.JCI insight · 2019Pooled it
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- Successful Isoproterenol Treatment for Ventricular Fibrillation Storm in Early Repolarization Syndrome With SCN5A Mutation.Annals of noninvasive electrocardiology : the official journal of the International Society for Holter and Noninvasive Electrocardiology, Inc · 2026Article
- Genetic Basis of Brugada Syndrome.Biomedicines · 2025Review
- The Role of Human-Induced Pluripotent Stem Cells in Studying Cardiac Channelopathies.International journal of molecular sciences · 2024Review
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- NovelExperimental and therapeutic medicine · 2023Article
- Sudden Cardiac Death Risk Stratification of the Early Repolarization Syndrome: An Updated Review of the Literature.Current cardiology reports · 2023Review
- Personalized Therapeutics for KAnnual review of pharmacology and toxicology · 2023Review
- Mechanisms underlying the antiarrhythmic effect of ARumenamide-787 in experimental models of the J wave syndromes and hypothermia.PloS one · 2023Article
- Kir6.1 and SUR2B in Cantú syndrome.American journal of physiology. Cell physiology · 2022Review
- European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases.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 · 2022Article
- European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases.Journal of arrhythmia · 2022Article
- Brugada Syndrome: Different Experimental Models and the Role of Human Cardiomyocytes From Induced Pluripotent Stem Cells.Journal of the American Heart Association · 2022Review
17 more citing papers are in PubMed but not listed here.
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Authors and funding
18 authors at 6 institutions in 4 countries.
Funding
Abstract
backgroundAdenosine triphosphate (ATP)-sensitive potassium cardiac channels consist of inward-rectifying channel subunits Kir6.1 or Kir6.2 (encoded by KCNJ8 or KCNJ11) and the sulfonylurea receptor subunits SUR2A (encoded by ABCC9).
objectiveTo examine the association of mutations in KCNJ8 with Brugada syndrome (BrS) and early repolarization syndrome (ERS) and to elucidate the mechanism underlying the gain of function of ATP-sensitive potassium channel current.
methodsDirect sequencing of KCNJ8 and other candidate genes was performed on 204 BrS and ERS probands and family members. Whole-cell and inside-out patch-clamp methods were used to study mutated channels expressed in TSA201 cells.
resultsThe same missense mutation, p.Ser422Leu (c.1265C>T) in KCNJ8, was identified in 3 BrS and 1 ERS probands but was absent in 430 alleles from ethnically matched healthy controls. Additional genetic variants included CACNB2b-D601E. Whole-cell patch-clamp studies showed a 2-fold gain of function of glibenclamide-sensitive ATP-sensitive potassium channel current when KCNJ8-S422L was coexpressed with SUR2A-wild type. Inside-out patch-clamp evaluation yielded a significantly greater half maximal inhibitory concentration for ATP in the mutant channels (785.5 ± 2 vs 38.4 ± 3 μM; n = 5; P <.01), pointing to incomplete closing of the ATP-sensitive potassium channels under normoxic conditions. Patients with a CACNB2b-D601E polymorphism displayed longer QT/corrected QT intervals, likely owing to their effect to induce an increase in L-type calcium channel current (I(Ca-L)).
conclusionsOur results support the hypothesis that KCNJ8 is a susceptibility gene for BrS and ERS and point to S422L as a possible hotspot mutation. Our findings suggest that the S422L-induced gain of function in ATP-sensitive potassium channel current is due to reduced sensitivity to intracellular ATP.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.