Loss-of-function of the voltage-gated sodium channel NaV1.5 (channelopathies) in patients with irritable bowel syndrome

Gastroenterology. 2014 Jun;146(7):1659-1668. doi: 10.1053/j.gastro.2014.02.054. Epub 2014 Mar 5.


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.

Trial registration: ClinicalTrials.gov NCT01717404.

Keywords: GI Motility; Genetics; Polymorphism; Voltage-Gated Sodium Channel.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Case-Control Studies
  • Channelopathies / diagnosis
  • Channelopathies / drug therapy
  • Channelopathies / epidemiology
  • Channelopathies / genetics*
  • Channelopathies / metabolism
  • Channelopathies / physiopathology
  • Constipation / epidemiology
  • Constipation / genetics
  • Constipation / metabolism
  • Constipation / physiopathology
  • DNA Mutational Analysis
  • Diarrhea / epidemiology
  • Diarrhea / genetics
  • Diarrhea / metabolism
  • Diarrhea / physiopathology
  • Female
  • Gastrointestinal Motility* / drug effects
  • Gastrointestinal Motility* / genetics
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • HEK293 Cells
  • Humans
  • Irritable Bowel Syndrome / diagnosis
  • Irritable Bowel Syndrome / drug therapy
  • Irritable Bowel Syndrome / epidemiology
  • Irritable Bowel Syndrome / genetics*
  • Irritable Bowel Syndrome / metabolism
  • Irritable Bowel Syndrome / physiopathology
  • Male
  • Membrane Potentials
  • Middle Aged
  • Mutation, Missense*
  • NAV1.5 Voltage-Gated Sodium Channel / drug effects
  • NAV1.5 Voltage-Gated Sodium Channel / genetics*
  • NAV1.5 Voltage-Gated Sodium Channel / metabolism
  • Phenotype
  • Prevalence
  • Prospective Studies
  • Risk Factors
  • Transfection
  • Voltage-Gated Sodium Channel Blockers / therapeutic use
  • Young Adult


  • NAV1.5 Voltage-Gated Sodium Channel
  • SCN5A protein, human
  • Voltage-Gated Sodium Channel Blockers

Associated data

  • ClinicalTrials.gov/NCT01717404