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NEUROREGULATION AND MOTILITY

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

¹Enteric Neuroscience Program, ²Departments of Medicine (Cardiovascular Diseases), Pediatrics (Pediatric Cardiology), and Molecular Pharmacology and Experimental Therapeutics and the Windland Smith Rice Sudden Death Genomics Laboratory, and ³Miles and Shirley Fiterman Center for Digestive Diseases, Mayo Clinic, Rochester, Minnesota; and ⁴Department of Medicine, University of Wisconsin, Madison, Wisconsin

Submitted 1 October 2008 ; accepted in final form 24 November 2008

The SCN5A-encoded Na_v1.5 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.

SCN5A; Na_v1.5; current density; mechanosensitivity