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Loss-of-Function of the Voltage-Gated Sodium Channel Na(V)1.5 (Channelopathies) in Patients With Irritable Bowel Syndrome

Beyder, Arthur; Mazzone, Amelia; Strege, Peter R.; Tester, David J.; Saito, Yuri A.; Bernard, Cheryl E.; Enders, Felicity T.; Ek, Weronica E.; Schmidt, Peter T. and Dlugosz, Aldona, et al. (2014) In Gastroenterology 146(7). p.1659-1668
Abstract
BACKGROUND & AIMS: SCN5A encodes the a-subunit of the voltage-gated sodium channel Na(V)1.5. 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 Na(V)1.5. 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... (More)
BACKGROUND & AIMS: SCN5A encodes the a-subunit of the voltage-gated sodium channel Na(V)1.5. 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 Na(V)1.5. 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 Na(V)1.5 function (9 loss-of-function and 1 gain-of-function function). The p. A997T-Na(V)1.5 had the greatest effect in reducing Na(V)1.5 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 Na(V)1.5 channel function. These findings provide a new pathogenic mechanism for IBS and possible treatment options. (Less)
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@article{ec223874-145f-427d-b7c7-3ccd666c175b,
  abstract     = {BACKGROUND &amp; AIMS: SCN5A encodes the a-subunit of the voltage-gated sodium channel Na(V)1.5. 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 Na(V)1.5. 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 &lt; .05). Electrophysiologic analysis showed that 10 of 13 detected mutations disrupted Na(V)1.5 function (9 loss-of-function and 1 gain-of-function function). The p. A997T-Na(V)1.5 had the greatest effect in reducing Na(V)1.5 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 Na(V)1.5 channel function. These findings provide a new pathogenic mechanism for IBS and possible treatment options.},
  author       = {Beyder, Arthur and Mazzone, Amelia and Strege, Peter R. and Tester, David J. and Saito, Yuri A. and Bernard, Cheryl E. and Enders, Felicity T. and Ek, Weronica E. and Schmidt, Peter T. and Dlugosz, Aldona and Lindberg, Greger and Karling, Pontus and Ohlsson, Bodil and Gazouli, Maria and Nardone, Gerardo and Cuomo, Rosario and Usai-Satta, Paolo and Galeazzi, Francesca and Neri, Matteo and Portincasa, Piero and Bellini, Massimo and Barbara, Giovanni and Camilleri, Michael and Locke III, G. Richard and Talley, Nicholas J. and D'Amato, Mauro and Ackerman, Michael J. and Farrugia, Gianrico},
  issn         = {1528-0012},
  keyword      = {Genetics,GI Motility,Voltage-Gated Sodium Channel,Polymorphism},
  language     = {eng},
  number       = {7},
  pages        = {1659--1668},
  publisher    = {W B Saunders},
  series       = {Gastroenterology},
  title        = {Loss-of-Function of the Voltage-Gated Sodium Channel Na(V)1.5 (Channelopathies) in Patients With Irritable Bowel Syndrome},
  url          = {http://dx.doi.org/10.1053/j.gastro.2014.02.054},
  volume       = {146},
  year         = {2014},
}