ArticlePhysiological genomics2011
The common African American polymorphism SCN5A-S1103Y interacts with mutation SCN5A-R680H to increase late Na current.
Article in Physiological genomics, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers, 1 of them a synthesis that pooled it.
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Who cites it
19 citing papers in PubMed, 1 synthesis or guideline pooled it, 35 citations in OpenAlex.
- Variability in reported midpoints of (in)activation of cardiac INa.The Journal of general physiology · 2025Pooled it
- Common genetic variants of the cardiac sodium channel alter patient response to class 1b antiarrhythmics.Journal of precision medicine (Amsterdam, Netherlands) · 2026Article
- Common Genetic Variants of The Cardiac Sodium Channel Alter Patient Response to Class 1b Antiarrhythmics.bioRxiv : the preprint server for biology · 2026Article
- Investigating the role of the I-II linker in Nav1.5 channel function.The Journal of general physiology · 2025Article
- Exploring Atrial Fibrillation: Understanding the Complex Relation Between Lifestyle and Genetic Factors.Journal of medical cases · 2024Article
- Genomic analysis of an Ecuadorian individual carrying an SCN5A rare variant.BMC cardiovascular disorders · 2024Article
- Addressing Disparities in Pediatric Congenital Heart Disease: A Call for Equitable Health Care.Journal of the American Heart Association · 2024Review
- Challenges in Brugada Syndrome Stratification: InvestigatingInternational journal of molecular sciences · 2023Article
- Clinical Genetics of Inherited Arrhythmogenic Disease in the Pediatric Population.Biomedicines · 2022Review
- Cannabinoid-Induced Brugada Syndrome: A Case Report.Cureus · 2020Article
- Next-generation sequencing using microfluidic PCR enrichment for molecular autopsy.BMC cardiovascular disorders · 2019Article
- An African loss-of-function CACNA1C variant p.T1787M associated with a risk of ventricular fibrillation.Scientific reports · 2018Article
- Channelopathy as a SUDEP Biomarker in Dravet Syndrome Patient-Derived Cardiac Myocytes.Stem cell reports · 2018Article
- Depolarization of the conductance-voltage relationship in the NaV1.5 mutant, E1784K, is due to altered fast inactivation.PloS one · 2017Article
- The biophysical characterization of the first SCN5A mutation R1512W identified in Chinese sudden unexplained nocturnal death syndrome.Medicine · 2016Observational
- Arrhythmogenic Biophysical Phenotype for SCN5A Mutation S1787N Depends upon Splice Variant Background and Intracellular Acidosis.PloS one · 2015Article
- Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease.Human genetics · 2013Review
- Playing with heart and soul…and genomes: sports implications and applications of personal genomics.PeerJ · 2013Article
- Cardiac channelopathy causing sudden death as revealed by molecular autopsy.International journal of legal medicine · 2013Article
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
The common polymorphism SCN5A-S1103Y (∼13% allelic frequency in African Americans) is a risk factor for arrhythmia, sudden unexplained death (SUD), and sudden infant death syndrome. Prompted by a case of autopsy-negative SUD in a 23-year-old African American man who collapsed while playing football, we hypothesized that S1103Y interacted with other SCN5A variants to pathologically modify sodium current (I(Na)). Mutational analysis of arrhythmia-associated genes in the victim revealed the variants SCN5A-R680H and SCN5A-S1103Y. These variants were made both separately and in the same cDNA construct of the alternative splice variant backgrounds (SCN5A-Q1077del and Q1077) and expressed in HEK293 cells. In the most abundant SCN5A-Q1077del, late I(Na) for S1103Y alone was not significantly different from wild type (WT). However, late I(Na) for R680H, R680H+S1103Y (coexpressed), and R680H/S1103Y (on the same cDNA) was increased 2.1-, 3.4-, and 3.6-fold, respectively, compared with WT. Intracellular acidosis (pH 6.7) increased late I(Na) for S1103Y, R680H, R680H+S1103Y, and R680H/S1103Y by 2.2-, 2.4-, 5.0-, and 5.5-fold, respectively, compared with WT at pH 6.7. Expression in the less abundant SCN5A-Q1077 showed no increased late I(Na). This is the initial report of a functional interaction for the common polymorphism S1103Y with another mutation in the major transcript Q1077del of SCN5A. The "double hit" and environmental factor of acidosis may have converged to cause arrhythmic sudden death in this case.
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