ArticleActa physiologica (Oxford, England)2008
Correlations between clinical and physiological consequences of the novel mutation R878C in a highly conserved pore residue in the cardiac Na+ channel.
Article in Acta physiologica (Oxford, England), 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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19 citing papers in PubMed, 36 citations in OpenAlex.
- Characterization of the R893C NaFrontiers in cardiovascular medicine · 2026Article
- SCN10A-short gene therapy to restore conduction and protect against malignant cardiac arrhythmias.European heart journal · 2025Article
- Mapping structural distribution and gating-property impacts of disease-associated mutations in voltage-gated sodium channels.iScience · 2024Article
- Biophysical mechanisms of myocardium sodium channelopathies.Pflugers Archiv : European journal of physiology · 2024Review
- Inhibitory Effects of Nobiletin on Voltage-Gated NaInternational journal of molecular sciences · 2022Article
- Novel SCN5A variants identified in a group of Iranian Brugada syndrome patients.Functional & integrative genomics · 2021Article
- Inter-Regulation of KInternational journal of molecular sciences · 2020Article
- Reevaluating the Mutation Classification in Genetic Studies of Bradycardia Using ACMG/AMP Variant Classification Framework.International journal of genomics · 2020Article
- Brugada syndrome trafficking-defective Nav1.5 channels can trap cardiac Kir2.1/2.2 channels.JCI insight · 2018Article
- Sinus Bradycardia in Carriers of the SCN5A-1795insD Mutation: Unraveling the Mechanism through Computer Simulations.International journal of molecular sciences · 2018Article
- Murine Electrophysiological Models of Cardiac Arrhythmogenesis.Physiological reviews · 2017Review
- SCN4A variants and Brugada syndrome: phenotypic and genotypic overlap between cardiac and skeletal muscle sodium channelopathies.European journal of human genetics : EJHG · 2016Article
- The genetic basis for inherited forms of sinoatrial dysfunction and atrioventricular node dysfunction.Journal of interventional cardiac electrophysiology : an international journal of arrhythmias and pacing · 2015Review
- Novel SCN5A mutations in two families with "Brugada-like" ST elevation in the inferior leads and conduction disturbances.Journal of interventional cardiac electrophysiology : an international journal of arrhythmias and pacing · 2013Article
- Characterization of N-terminally mutated cardiac Na(+) channels associated with long QT syndrome 3 and Brugada syndrome.Frontiers in physiology · 2013Article
- Dominant-negative effect of SCN5A N-terminal mutations through the interaction of Na(v)1.5 α-subunits.Cardiovascular research · 2012Article
- Alternative splicing of the cardiac sodium channel creates multiple variants of mutant T1620K channels.PloS one · 2011Article
- Multiple loss-of-function mechanisms contribute to SCN5A-related familial sick sinus syndrome.PloS one · 2010Article
- Sodium channel mutations and arrhythmias.Nature reviews. Cardiology · 2009Review
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Authors and funding
14 authors at 4 institutions in 3 countries.
Funding
Abstract
aimWe compared the clinical and physiological consequences of the novel mutation R878C in a highly conserved pore residue in domain II (S5-S6) of human, hNa(v)1.5, cardiac Na(+) channels.
methodsFull clinical evaluation of pedigree members through three generations of a Chinese family combined with SCN5A sequencing from genomic DNA was compared with patch and voltage-clamp results from two independent expression systems.
resultsThe four mutation carriers showed bradycardia, and slowed sino-atrial, atrioventricular and intraventricular conduction. Two also showed sick sinus syndrome; two had ST elevation in leads V1 and V2. Unlike WT-hNa(v)1.5, whole-cell patch-clamped HEK293 cells expressing R878C-hNa(v)1.5 showed no detectable Na(+) currents (i(Na)), even with substitution of a similarly charged lysine residue. Voltage-clamped Xenopus oocytes injected with either 0.04 or 1.5 microg microL(-1) R878C-hNa(v)1.5 cRNA similarly showed no i(Na), yet WT-hNa(v)1.5 cRNA diluted to 0.0004-0.0008 ng microL(-1)resulted in expression of detectable i(Na). i(Na) was simply determined by the amount of injected WT-hNa(v)1.5: doubling the dose of WT-hNa(v)1.5 cRNA doubled i(Na). i(Na) amplitudes and activation and inactivation characteristics were similar irrespective of whether WT-hNa(v)1.5 cRNA was given alone or combined with equal doses of R878C-hNa(v)1.5 cRNA therefore excluding dominant negative phenotypic effects. Na(+) channel function in HEK293 cells transfected with R878C-hNa(v)1.5 was not restored by exposure to mexiletine (200 microM) and lidocaine (100 microM). Fluorescence confocal microscopy using E3-Nav1.5 antibody demonstrated persistent membrane expression of both WT and R878C-hNa(v)1.5. Modelling studies confirmed that such i(Na) reductions reproduced the SSS phenotype.
conclusionClinical consequences of the novel R878C mutation correlate with results of physiological studies.
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