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

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(v)1.5 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(v)1.5 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(v)1.5, suggesting SCN5A as a candidate gene in the pathophysiology of IBS.

Therapeutic strategies for functional dyspepsia and irritable bowel syndrome based on pathophysiology

“…Homozygous GNB3 825C carrier status is associated with unexplained upper abdominal symptoms in FD [35] and is linked to predominant EPStype FD in a Japanese population [36]. In IBS, a mutation identified in the Na v 1.5 sodium channel gene (SCN5A) has been identified in IBS [37], and may explain up to 2 % of IBS cases. Importantly, the sodium channel changes may be amenable to pharmacological intervention as suggested by a proof-of-principle study in one patient.…”

Pain as a channelopathy

“…The Na v 1.5 voltage-gated sodium channel encoded by SCN5A is expressed in human jejunal epithelial cells and interstitial cells of Cajal (68). In a study of an IBS cohort, one patient with a family history of IBS exhibited a loss-of-function G298S missense mutation on a background of a common H558R polymorphism in SCN5A (69). The G298S mutation results in a reduction in the current density, slowing of the activation kinetics, and possibly reduced mechanosensitivity of the channel on H558R background (69).…”

“…In a study of an IBS cohort, one patient with a family history of IBS exhibited a loss-of-function G298S missense mutation on a background of a common H558R polymorphism in SCN5A (69). The G298S mutation results in a reduction in the current density, slowing of the activation kinetics, and possibly reduced mechanosensitivity of the channel on H558R background (69). Further studies are needed to establish an association of SCN5A channelopathies with IBS symptoms.…”

Targeting Ion Channels: An Important Therapeutic Implication in Gastrointestinal Dysmotility in Patients With Spinal Cord Injury

“…For example people with mutations in SCN5A have higher prevalence of Brugada syndrome and functional dyspepsia, 7 as well as irritable bowel syndrome (IBS). 8 Thus agents directly regulating ion channel activities either in ICC or in SMCs may affect the GI peristalsis. 9 For example, certain potassium channel blockers and compounds increasing Ca 2+ release or Ca 2+ sensitivity specifically acting on GI tract would be potentially effective therapeutic agents for GI dysmotility.…”