ArticlePloS one2010
Multiple loss-of-function mechanisms contribute to SCN5A-related familial sick sinus syndrome.
Article in PloS one, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 47 papers, 1 of them a synthesis that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
47 citing papers in PubMed, 1 synthesis or guideline pooled it, 82 citations in OpenAlex.
- Variability in reported midpoints of (in)activation of cardiac INa.The Journal of general physiology · 2025Pooled it
- Cardiac Arrest in a Young Soccer Player With a Pathogenic SCN5A Variant.JACC. Case reports · 2026Article
- SCN5AInternational journal of legal medicine · 2026Article
- Ventricular ion channels and arrhythmias: an overview of physiology, pathophysiology and pharmacology.Medical review (2021) · 2025Review
- SCN10A-short gene therapy to restore conduction and protect against malignant cardiac arrhythmias.European heart journal · 2025Article
- Charge Reversal of the Uppermost Arginine in Sliding Helix S4-I Affects Gating of Cardiac Sodium Channel.International journal of molecular sciences · 2025Article
- Multisite Validation of a Functional Assay to AdjudicateCirculation. Genomic and precision medicine · 2024Article
- Multi-site validation of a functional assay to adjudicatemedRxiv : the preprint server for health sciences · 2023Article
- Development of automated patch clamp assays to overcome the burden of variants of uncertain significance in inheritable arrhythmia syndromes.Frontiers in physiology · 2023Review
- Dominant negative effects of SCN5A missense variants.Genetics in medicine : official journal of the American College of Medical Genetics · 2022Article
- Article
- Clinical Spectrum ofGenes · 2021Article
- Novel SCN5A variants identified in a group of Iranian Brugada syndrome patients.Functional & integrative genomics · 2021Article
- Familial sick sinus syndrome possibly associated with novelHeartRhythm case reports · 2021Article
- High-Throughput Reclassification of SCN5A Variants.American journal of human genetics · 2020Article
- Role of the voltage sensor module in NaChannels (Austin, Tex.) · 2019Review
- Genotype/Phenotype Relationship in a Consanguineal Family With Brugada Syndrome Harboring the R1632C Missense Variant in theFrontiers in physiology · 2019Article
- Mutations in NaFrontiers in physiology · 2019Article
- Protein structure aids predicting functional perturbation of missense variants inComputational and structural biotechnology journal · 2019Article
- Mechanistic insights into the interaction of the MOG1 protein with the cardiac sodium channel NaThe Journal of biological chemistry · 2018Article
Corrections and comments
- Erratum issued
- Erratum issued
Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
backgroundTo identify molecular mechanisms underlying SCN5A-related sick sinus syndrome (SSS), a rare type of SSS, in parallel experiments we elucidated the electrophysiological properties and the cell surface localization of thirteen human Na(v)1.5 (hNa(v)1.5) mutant channels previously linked to this disease. METHODOLOGY/PRINCIPAL
findingsMutant hNa(v)1.5 channels expressed by HEK293 cells and Xenopus oocytes were investigated by whole-cell patch clamp and two-microelectrode voltage clamp, respectively. HEK293 cell surface biotinylation experiments quantified the fraction of correctly targeted channel proteins. Our data suggested three distinct mutant channel subtypes: Group 1 mutants (L212P, P1298L, DelF1617, R1632H) gave peak current densities and cell surface targeting indistinguishable from wild-type hNa(v)1.5. Loss-of-function of these mutants resulted from altered channel kinetics, including a negative shift of steady-state inactivation and a reduced voltage dependency of open-state inactivation. Group 2 mutants (E161K, T220I, D1275N) gave significantly reduced whole-cell currents due to impaired cell surface localization (D1275N), altered channel properties at unchanged cell surface localization (T220I), or a combination of both (E161K). Group 3 mutant channels were non-functional, due to an almost complete lack of protein at the plasma membrane (T187I, W1421X, K1578fs/52, R1623X) or a probable gating/permeation defect with normal surface localisation (R878C, G1408R). CONCLUSIONS/SIGNIFICANCE: This study indicates that multiple molecular mechanisms, including gating abnormalities, trafficking defects, or a combination of both, are responsible for SCN5A-related familial SSS.
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Registered trials
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.