Sodium channel mutation in irritable bowel syndrome: Evidence for an ion channelopathy

Yuri Ann Saito Loftus, Peter R. Strege, David J. Tester, G. Richard Locke, Nicholas J. Talley, Cheryl E. Bernard, James L. Rae, Jonathan C. Makielski, Michael John Ackerman, Gianrico Farrugia

Research output: Contribution to journalArticle

80 Citations (Scopus)

Abstract

The SCN5A-encoded Na v 1.5 Na + channel is expressed in interstitial cells of Cajal and smooth muscle in the circular layer of the human intestine. Patients with mutations in SCN5A are more likely to report gastrointestinal symptoms, especially abdominal pain. Twin and family studies of irritable bowel syndrome (IBS) suggest a genetic basis for IBS, but no genes have been identified to date. Therefore, our aims were to evaluate SCN5A as a candidate gene involved in the pathogenesis of IBS and to determine physiological consequences of identified mutations. Mutational analysis was performed on genomic DNA obtained from 49 subjects diagnosed with IBS who reported at least moderately severe abdominal pain. One patient hosted a loss-of-function missense mutation, G298S, that was not observed in >3,000 reference alleles derived from 1,500 healthy control subjects. Na + currents were recorded from the four common human SCN5A transcripts in transfected HEK-293 cells. Comparing Na v1.5 with G298S-SCN5A versus wild type in HEK cells, Na + current density was significantly less by 49-77%, and channel activation time was delayed in backgrounds that also contained the common H558R polymorphism. Single-channel measurements showed no change in Na v1.5 conductance. Mechanosensitivity was reduced in the H558/Q1077del transcript but not in the other three backgrounds. In conclusion, the G298S-SCN5A missense mutation caused a marked reduction of whole cell Na + current and loss of function of Na v1.5, suggesting SCN5A as a candidate gene in the pathophysiology of IBS.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume296
Issue number2
DOIs
StatePublished - Feb 2009

Fingerprint

Channelopathies
Sodium Channels
Irritable Bowel Syndrome
Ions
Mutation
Missense Mutation
Abdominal Pain
Interstitial Cells of Cajal
Genes
Twin Studies
HEK293 Cells
Intestines
Smooth Muscle
Healthy Volunteers
Alleles
DNA

Keywords

  • Current density
  • Mechanosensitivity
  • Na 1.5
  • SCNJA

ASJC Scopus subject areas

  • Gastroenterology
  • Physiology (medical)
  • Physiology
  • Hepatology

Cite this

Sodium channel mutation in irritable bowel syndrome : Evidence for an ion channelopathy. / Saito Loftus, Yuri Ann; Strege, Peter R.; Tester, David J.; Locke, G. Richard; Talley, Nicholas J.; Bernard, Cheryl E.; Rae, James L.; Makielski, Jonathan C.; Ackerman, Michael John; Farrugia, Gianrico.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 296, No. 2, 02.2009.

Research output: Contribution to journalArticle

Saito Loftus, Yuri Ann ; Strege, Peter R. ; Tester, David J. ; Locke, G. Richard ; Talley, Nicholas J. ; Bernard, Cheryl E. ; Rae, James L. ; Makielski, Jonathan C. ; Ackerman, Michael John ; Farrugia, Gianrico. / Sodium channel mutation in irritable bowel syndrome : Evidence for an ion channelopathy. In: American Journal of Physiology - Gastrointestinal and Liver Physiology. 2009 ; Vol. 296, No. 2.
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AU - Locke, G. Richard

AU - Talley, Nicholas J.

AU - Bernard, Cheryl E.

AU - Rae, James L.

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AU - Ackerman, Michael John

AU - Farrugia, Gianrico

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