ArticleGastroenterology2014
Loss-of-function of the voltage-gated sodium channel NaV1.5 (channelopathies) in patients with irritable bowel syndrome.
Article in Gastroenterology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 78 papers, 3 of them syntheses that pooled it.
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Who cites it
78 citing papers in PubMed, 3 syntheses or guidelines pooled it, 145 citations in OpenAlex.
- Pooled it
- Variability in reported midpoints of (in)activation of cardiac INa.The Journal of general physiology · 2025Pooled it
- Candidate single nucleotide polymorphisms of irritable bowel syndrome: a systemic review and meta-analysis.BMC gastroenterology · 2019Pooled it
- Trial
- Late IMedicinal research reviews · 2026Review
- Investigating the role of the I-II linker in Nav1.5 channel function.The Journal of general physiology · 2025Article
- Resistant Starch and Microbiota-Derived Secondary Metabolites: A Focus on Postbiotic Pathways in Gut Health and Irritable Bowel Syndrome.International journal of molecular sciences · 2025Review
- Study on the Therapeutic Effects and Mechanisms of Gintonin in Irritable Bowel Syndrome and Its Relationship with TRPV1, TRPV4, and NaV1.5.Pharmaceuticals (Basel, Switzerland) · 2024Article
- Biophysical mechanisms of myocardium sodium channelopathies.Pflugers Archiv : European journal of physiology · 2024Review
- The Role of Ion Channels in Functional Gastrointestinal Disorders (FGID): Evidence of Channelopathies and Potential Avenues for Future Research and Therapeutic Targets.International journal of molecular sciences · 2023Review
- Review
- Assessing the relationship between gut microbiota and irritable bowel syndrome: a two-sample Mendelian randomization analysis.BMC gastroenterology · 2023Article
- The neurobiology of irritable bowel syndrome.Molecular psychiatry · 2023Review
- Article
- Tracking Gut Motility in Organ and Cultures.Methods in molecular biology (Clifton, N.J.) · 2023Article
- Loose ends in the differential diagnosis of IBS-like symptoms.Frontiers in medicine · 2023Article
- Biobanking as a Tool for Genomic Research: From Allele Frequencies to Cross-Ancestry Association Studies.Journal of personalized medicine · 2022Review
- Capsaicin as an amphipathic modulator of NaChannels (Austin, Tex.) · 2022Article
- Genetics of irritable bowel syndrome: shifting gear via biobank-scale studies.Nature reviews. Gastroenterology & hepatology · 2022Review
- Digital Therapeutics Care Utilizing Genetic and Gut Microbiome Signals for the Management of Functional Gastrointestinal Disorders: Results From a Preliminary Retrospective Study.Frontiers in microbiology · 2022Article
18 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
28 authors at 12 institutions in 4 countries.
Funding
Abstract
BACKGROUND &
aimsSCN5A encodes the α-subunit of the voltage-gated sodium channel NaV1.5. Many patients with cardiac arrhythmias caused by mutations in SCN5A also have symptoms of irritable bowel syndrome (IBS). We investigated whether patients with IBS have SCN5A variants that affect the function of NaV1.5.
methodsWe performed genotype analysis of SCN5A in 584 persons with IBS and 1380 without IBS (controls). Mutant forms of SCN5A were expressed in human embryonic kidney-293 cells, and functions were assessed by voltage clamp analysis. A genome-wide association study was analyzed for an association signal for the SCN5A gene, and replicated in 1745 patients in 4 independent cohorts of IBS patients and controls.
resultsMissense mutations were found in SCN5A in 13 of 584 patients (2.2%, probands). Diarrhea-predominant IBS was the most prevalent form of IBS in the overall study population (25%). However, a greater percentage of individuals with SCN5A mutations had constipation-predominant IBS (31%) than diarrhea-predominant IBS (10%; P < .05). Electrophysiologic analysis showed that 10 of 13 detected mutations disrupted NaV1.5 function (9 loss-of-function and 1 gain-of-function function). The p. A997T-NaV1.5 had the greatest effect in reducing NaV1.5 function. Incubation of cells that expressed this variant with mexiletine restored their sodium current and administration of mexiletine to 1 carrier of this mutation (who had constipation-predominant IBS) normalized their bowel habits. In the genome-wide association study and 4 replicated studies, the SCN5A locus was strongly associated with IBS.
conclusionsAbout 2% of patients with IBS carry mutations in SCN5A. Most of these are loss-of-function mutations that disrupt NaV1.5 channel function. These findings provide a new pathogenic mechanism for IBS and possible treatment options.
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