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

Arthur Beyder, Amelia Mazzone, Peter R. Strege, David J. Tester, Yuri Ann Saito Loftus, Cheryl E. Bernard, Felicity T Enders, Weronica E. Ek, Peter T. Schmidt, Aldona Dlugosz, Greger Lindberg, Pontus Karling, Bodil Ohlsson, Maria Gazouli, Gerardo Nardone, Rosario Cuomo, Paolo Usai-Satta, Francesca Galeazzi, Matteo Neri, Piero PortincasaMassimo Bellini, Giovanni Barbara, Michael Camilleri, G. Richard Locke, Nicholas J. Talley, Mauro D'Amato, Michael John Ackerman, Gianrico Farrugia

Research output: Contribution to journalArticle

52 Citations (Scopus)

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 Na V1.5 channel function. These findings provide a new pathogenic mechanism for IBS and possible treatment options.

Original languageEnglish (US)
Pages (from-to)1659-1668
Number of pages10
JournalGastroenterology
Volume146
Issue number7
DOIs
StatePublished - 2014

Fingerprint

NAV1.5 Voltage-Gated Sodium Channel
Channelopathies
Irritable Bowel Syndrome
Mutation
Mexiletine
Genome-Wide Association Study
Constipation
Diarrhea

Keywords

  • Genetics
  • GI Motility
  • Polymorphism
  • Voltage-Gated Sodium Channel

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Loss-of-function of the voltage-gated sodium channel NaV1.5 (Channelopathies) in patients with irritable bowel syndrome. / Beyder, Arthur; Mazzone, Amelia; Strege, Peter R.; Tester, David J.; Saito Loftus, Yuri Ann; Bernard, Cheryl E.; Enders, Felicity T; Ek, Weronica E.; Schmidt, Peter T.; Dlugosz, Aldona; Lindberg, Greger; Karling, Pontus; Ohlsson, Bodil; Gazouli, Maria; Nardone, Gerardo; Cuomo, Rosario; Usai-Satta, Paolo; Galeazzi, Francesca; Neri, Matteo; Portincasa, Piero; Bellini, Massimo; Barbara, Giovanni; Camilleri, Michael; Locke, G. Richard; Talley, Nicholas J.; D'Amato, Mauro; Ackerman, Michael John; Farrugia, Gianrico.

In: Gastroenterology, Vol. 146, No. 7, 2014, p. 1659-1668.

Research output: Contribution to journalArticle

Beyder, A, Mazzone, A, Strege, PR, Tester, DJ, Saito Loftus, YA, Bernard, CE, Enders, FT, Ek, WE, Schmidt, PT, 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, GR, Talley, NJ, D'Amato, M, Ackerman, MJ & Farrugia, G 2014, 'Loss-of-function of the voltage-gated sodium channel NaV1.5 (Channelopathies) in patients with irritable bowel syndrome', Gastroenterology, vol. 146, no. 7, pp. 1659-1668. https://doi.org/10.1053/j.gastro.2014.02.054
Beyder, Arthur ; Mazzone, Amelia ; Strege, Peter R. ; Tester, David J. ; Saito Loftus, Yuri Ann ; Bernard, Cheryl E. ; Enders, Felicity T ; Ek, Weronica E. ; Schmidt, Peter T. ; Dlugosz, Aldona ; Lindberg, Greger ; Karling, Pontus ; Ohlsson, Bodil ; Gazouli, Maria ; Nardone, Gerardo ; Cuomo, Rosario ; Usai-Satta, Paolo ; Galeazzi, Francesca ; Neri, Matteo ; Portincasa, Piero ; Bellini, Massimo ; Barbara, Giovanni ; Camilleri, Michael ; Locke, G. Richard ; Talley, Nicholas J. ; D'Amato, Mauro ; Ackerman, Michael John ; Farrugia, Gianrico. / Loss-of-function of the voltage-gated sodium channel NaV1.5 (Channelopathies) in patients with irritable bowel syndrome. In: Gastroenterology. 2014 ; Vol. 146, No. 7. pp. 1659-1668.
@article{f68b30d7e6b4450e8ff80309145d256f,
title = "Loss-of-function of the voltage-gated sodium channel NaV1.5 (Channelopathies) in patients with irritable bowel syndrome",
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 Na V1.5 channel function. These findings provide a new pathogenic mechanism for IBS and possible treatment options.",
keywords = "Genetics, GI Motility, Polymorphism, Voltage-Gated Sodium Channel",
author = "Arthur Beyder and Amelia Mazzone and Strege, {Peter R.} and Tester, {David J.} and {Saito Loftus}, {Yuri Ann} and Bernard, {Cheryl E.} and Enders, {Felicity T} and Ek, {Weronica E.} and Schmidt, {Peter T.} and Aldona Dlugosz and Greger Lindberg and Pontus Karling and Bodil Ohlsson and Maria Gazouli and Gerardo Nardone and Rosario Cuomo and Paolo Usai-Satta and Francesca Galeazzi and Matteo Neri and Piero Portincasa and Massimo Bellini and Giovanni Barbara and Michael Camilleri and Locke, {G. Richard} and Talley, {Nicholas J.} and Mauro D'Amato and Ackerman, {Michael John} and Gianrico Farrugia",
year = "2014",
doi = "10.1053/j.gastro.2014.02.054",
language = "English (US)",
volume = "146",
pages = "1659--1668",
journal = "Gastroenterology",
issn = "0016-5085",
publisher = "W.B. Saunders Ltd",
number = "7",

}

TY - JOUR

T1 - Loss-of-function of the voltage-gated sodium channel NaV1.5 (Channelopathies) in patients with irritable bowel syndrome

AU - Beyder, Arthur

AU - Mazzone, Amelia

AU - Strege, Peter R.

AU - Tester, David J.

AU - Saito Loftus, Yuri Ann

AU - Bernard, Cheryl E.

AU - Enders, Felicity T

AU - Ek, Weronica E.

AU - Schmidt, Peter T.

AU - Dlugosz, Aldona

AU - Lindberg, Greger

AU - Karling, Pontus

AU - Ohlsson, Bodil

AU - Gazouli, Maria

AU - Nardone, Gerardo

AU - Cuomo, Rosario

AU - Usai-Satta, Paolo

AU - Galeazzi, Francesca

AU - Neri, Matteo

AU - Portincasa, Piero

AU - Bellini, Massimo

AU - Barbara, Giovanni

AU - Camilleri, Michael

AU - Locke, G. Richard

AU - Talley, Nicholas J.

AU - D'Amato, Mauro

AU - Ackerman, Michael John

AU - Farrugia, Gianrico

PY - 2014

Y1 - 2014

N2 - 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 Na V1.5 channel function. These findings provide a new pathogenic mechanism for IBS and possible treatment options.

AB - 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 Na V1.5 channel function. These findings provide a new pathogenic mechanism for IBS and possible treatment options.

KW - Genetics

KW - GI Motility

KW - Polymorphism

KW - Voltage-Gated Sodium Channel

UR - http://www.scopus.com/inward/record.url?scp=84901230979&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84901230979&partnerID=8YFLogxK

U2 - 10.1053/j.gastro.2014.02.054

DO - 10.1053/j.gastro.2014.02.054

M3 - Article

C2 - 24613995

AN - SCOPUS:84901230979

VL - 146

SP - 1659

EP - 1668

JO - Gastroenterology

JF - Gastroenterology

SN - 0016-5085

IS - 7

ER -