title: Loss-of-function of the voltage-gated sodium channel NaV1.5 (channelopathies) in patients with irritable bowel syndrome.
abstract: OBJECTIVE
  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.
authors.affiliation: Enteric Neuroscience Program, Division of Gastroenterology &Hepatology, Department of Physiology & Biomedical Engineering, Mayo Clinic, Rochester, Minnesota.
authors.forename: Arthur
authors.initials: A
authors.lastname: Beyder
authors.affiliation: Enteric Neuroscience Program, Division of Gastroenterology &Hepatology, Department of Physiology & Biomedical Engineering, Mayo Clinic, Rochester, Minnesota.
authors.forename: Amelia
authors.initials: A
authors.lastname: Mazzone
authors.affiliation: Enteric Neuroscience Program, Division of Gastroenterology &Hepatology, Department of Physiology & Biomedical Engineering, Mayo Clinic, Rochester, Minnesota.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Strege
authors.affiliation: Departments of Medicine (Cardiovascular Diseases), Pediatrics (Pediatric Cardiology), and Molecular Pharmacology & Experimental Therapeutics and the Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota.
authors.forename: David J
authors.initials: DJ
authors.lastname: Tester
authors.affiliation: Enteric Neuroscience Program, Division of Gastroenterology &Hepatology, Department of Physiology & Biomedical Engineering, Mayo Clinic, Rochester, Minnesota.
authors.forename: Yuri A
authors.initials: YA
authors.lastname: Saito
authors.affiliation: Enteric Neuroscience Program, Division of Gastroenterology &Hepatology, Department of Physiology & Biomedical Engineering, Mayo Clinic, Rochester, Minnesota.
authors.forename: Cheryl E
authors.initials: CE
authors.lastname: Bernard
authors.affiliation: Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota.
authors.forename: Felicity T
authors.initials: FT
authors.lastname: Enders
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Weronica E
authors.initials: WE
authors.lastname: Ek
authors.affiliation: Department of Gastroenterology and Hepatology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Schmidt
authors.affiliation: Department of Gastroenterology and Hepatology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Aldona
authors.initials: A
authors.lastname: Dlugosz
authors.affiliation: Department of Gastroenterology and Hepatology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Greger
authors.initials: G
authors.lastname: Lindberg
authors.affiliation: Department of Medicine, Umeå University, Umeå, Sweden.
authors.forename: Pontus
authors.initials: P
authors.lastname: Karling
authors.affiliation: Department of Clinical Sciences, Skånes University Hospital, Malmoe, Sweden.
authors.forename: Bodil
authors.initials: B
authors.lastname: Ohlsson
authors.affiliation: Laboratory of Biology, School of Medicine, University of Athens, Athens, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Gazouli
authors.affiliation: Gastroenterology Unit, Department of Clinical Medicine and Surgery, University Federico II, Naples, Italy.
authors.forename: Gerardo
authors.initials: G
authors.lastname: Nardone
authors.affiliation: Digestive Motility Diseases, Department of Clinical Medicine and Surgery, Federico II University Hospital , Naples, Italy.
authors.forename: Rosario
authors.initials: R
authors.lastname: Cuomo
authors.affiliation: S.C. Gastroenterologia, Azienda Ospedaliera G. Brotzu, Cagliari, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Usai-Satta
authors.affiliation: UOC Gastroenterologia, Padova University Hospital, Padova, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Galeazzi
authors.affiliation: Department of Medicine and Aging Sciences and CESI, G. D'Annunzio University & Foundation, Chieti, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Neri
authors.affiliation: Department of Biomedical Sciences and Human Oncology (DIMO), Clinica Medica 'A. Murri', University of Bari Medical School, Bari, Italy.
authors.forename: Piero
authors.initials: P
authors.lastname: Portincasa
authors.affiliation: Gastroenterology Unit, Department of Gastroenterology, University of Pisa, Pisa, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Bellini
authors.affiliation: Department of Medical and Surgical Sciences, University of Bologna, St. Orsola - Malpighi Hospital, Bologna, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Barbara
authors.affiliation: Enteric Neuroscience Program, Division of Gastroenterology &Hepatology, Department of Physiology & Biomedical Engineering, Mayo Clinic, Rochester, Minnesota.
authors.forename: Michael
authors.initials: M
authors.lastname: Camilleri
authors.affiliation: Enteric Neuroscience Program, Division of Gastroenterology &Hepatology, Department of Physiology & Biomedical Engineering, Mayo Clinic, Rochester, Minnesota.
authors.forename: G Richard
authors.initials: GR
authors.lastname: Locke
authors.affiliation: Enteric Neuroscience Program, Division of Gastroenterology &Hepatology, Department of Physiology & Biomedical Engineering, Mayo Clinic, Rochester, Minnesota.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Talley
authors.affiliation: Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Mauro
authors.initials: M
authors.lastname: D'Amato
authors.affiliation: Departments of Medicine (Cardiovascular Diseases), Pediatrics (Pediatric Cardiology), and Molecular Pharmacology & Experimental Therapeutics and the Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, Minnesota.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Ackerman
authors.affiliation: Enteric Neuroscience Program, Division of Gastroenterology &Hepatology, Department of Physiology & Biomedical Engineering, Mayo Clinic, Rochester, Minnesota.
authors.forename: Gianrico
authors.initials: G
authors.lastname: Farrugia
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D053447:Channelopathies / Q000175:diagnosis / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D003248:Constipation / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D004252:DNA Mutational Analysis; D003967:Diarrhea / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D005769:Gastrointestinal Motility / Q000187:drug effects / Q000235:genetics; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D057809:HEK293 Cells; D006801:Humans; D043183:Irritable Bowel Syndrome / Q000175:diagnosis / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008564:Membrane Potentials; D008875:Middle Aged; D020125:Mutation, Missense; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D015995:Prevalence; D011446:Prospective Studies; D012307:Risk Factors; D014162:Transfection; D061567:Voltage-Gated Sodium Channel Blockers / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D061567:Voltage-Gated Sodium Channel Blockers
keywords: GI Motility; Genetics; Polymorphism; Voltage-Gated Sodium Channel