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Cited by 144Gastrointestinal motility and disordersIon channel regulation and functionCardiac electrophysiology and arrhythmias

Loss-of-Function of the Voltage-Gated Sodium Channel NaV1.5 (Channelopathies) in Patients With Irritable Bowel Syndrome

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Beyder, Arthur, Mazzone, Amelia, Strege, Peter R., Tester, David J., Saito, Yuri A., Bernard, Cheryl E., Enders, Felicity T., Ek, Weronica E. +20 more·2014·Gastroenterology
DOI 10.1053/j.gastro.2014.02.054PMC PMC4096335
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Abstract

Background & aims SCN5A 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. Methods We 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. Results Missense 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. Conclusions About 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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  • A subset of patients experience gastrointestinal symptoms first, and psychological distress later.

    “Prospective longitudinal studies demonstrate that a subset of patients experience gastrointestinal symptoms first, 23,24 and psychological distress later.”

    From Irritable bowel syndrome (2020) · cites this paper as [24]

    The Introduction and Results > IBS Patient Cohort (page numbers unavailable) discuss gastrointestinal symptoms and characterize patients with IBS, but do not address whether those symptoms preceded psychological distress. Searches for psychological distress, symptom onset, and prospective longitudinal findings found no passage establishing that sequence. (LLM, conf=0.76)

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Authors
Beyder, A., Mazzone, A., Strege, P. R., Tester, D. J., Saito, Y. A., Bernard, C. E., Enders, F. T., Ek, W. E., Schmidt, P. T., Dlugosz, A., Lindberg, G., Karling, P., Ohlsson, B., Gazouli, M., Nardone, G., Cuomo, R., Usai–Satta, P., Galeazzi, F., Neri, M., Portincasa, P., Bellini, M., Barbara, G., Camilleri, M., Locke, G. R., Talley, N. J., D’Amato, M., Ackerman, M. J., & Farrugia, G.
Affiliations
  • Mayo Clinic (US)
  • Karolinska Institutet (SE)
  • Karolinska University Hospital (SE)
  • Umeå University (SE)
  • Skåne University Hospital (SE)
  • National and Kapodistrian University of Athens (GR)
  • Federico II University Hospital (IT)
  • Azienda Ospedaliera G. Brotzu (IT)
  • University of Padua (IT)
  • University of Chieti-Pescara (IT)
  • University of Bari Aldo Moro (IT)
  • University of Pisa (IT)
  • IRCCS Azienda Ospedliero-Universitaria di Bologna Policlinico di Sant'Orsola (IT)
Corresponding author
  • Ackerman, Michael J.
  • Farrugia, Gianrico
ORCID
Venue
Gastroenterology
Publisher
Elsevier BV
Published
2014-06
Volume
146
Issue
7
Pages
1659-1668
ISSN
0016-5085 (ISSN-L)
DOI
10.1053/j.gastro.2014.02.054
PMC
PMC4096335
OpenAlex
W2003821675
Cited by
144
References
2
Citations by year
2026: 5 · 2025: 9 · 2024: 7 · 2023: 10 · 2022: 6 · 2021: 19 · 2020: 15 · 2019: 20 · 2018: 13 · 2017: 10 · 2016: 15 · 2015: 11 · 2014: 3
FWCI
13.03
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Gastroenterology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion)
  • Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
  • Lund University Publications (Lund University) (submittedVersion)
  • CINECA IRIS Institutional Research Information System (University of Bari Aldo Moro) (submittedVersion)
  • NOVA (University of Newcastle Australia) (submittedVersion)
Funders
  • Mayo Clinic
  • Boston Scientific Corporation
  • Georgia Clinical and Translational Science Alliance
  • Vetenskapsrådet (2010-02976)
  • National Institutes of Health
  • Center for Clinical and Translational Sciences, University of Texas Health Science Center at Houston
  • Center for Cell Signaling in Gastroenterology, Mayo Clinic
  • National Institute of Diabetes and Digestive and Kidney Diseases (DK52766, P30DK084567, R01DK052766)
Topics
  • Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
Keywords
irritable bowel syndrome, SCN5A, cardiac sodium channel, voltage-gated sodium channels, loss-of-function mutations, channelopathies, irritable bowel syndrome with constipation, diarrhea-predominant irritable bowel syndrome, mexiletine, sodium current, genotype-phenotype correlation, genetic susceptibility
MeSH terms
Adolescent, Adult, Aged, Constipation, Diarrhea, DNA Mutational Analysis, Female, Gastrointestinal Motility, Humans, Male, Membrane Potentials, Middle Aged, Phenotype, Prospective Studies, Risk Factors, Transfection, Prevalence, Case-Control Studies, Genetic Predisposition to Disease, Mutation, Missense, Irritable Bowel Syndrome, Channelopathies, Genome-Wide Association Study, Young Adult, HEK293 Cells, Voltage-Gated Sodium Channel Blockers, NAV1.5 Voltage-Gated Sodium Channel

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