Mutations Linked to IBS, May Lead to Treatment

Laurie Barclay, MD

March 26, 2014

Approximately 2% of patients with irritable bowel syndrome (IBS) have a mutation of the SCN5A gene that disrupts sodium channel function, according to a genotype analysis published online March 10 in Gastroenterology. This finding offers clues to a previously unknown pathogenic mechanism underlying IBS and possible treatment options.

"This gives us hope that from only treating symptoms of the disease, we can now work to find disease-modifying agents, which is where we really want to be to affect long-term treatment of IBS," senior author Gianrico Farrugia, MD, gastroenterologist and director of the Mayo Clinic Center for Individualized Medicine in Rochester, Minnesota, said in a clinic news release.

In the Western Hemisphere, estimated prevalence of IBS is about 15% to 20%. Most currently available treatments for IBS target the symptoms, which may include cramping, abdominal pain, bloating, gas, diarrhea, and constipation.

Previous theories concerning the etiology of IBS have suggested a role for diet, previous trauma, anxiety, and/or genetics, but this is the first report of a defined genetic mutation causing a subset of IBS. The culprit is a mutation of the SCN5A gene that affects the Nav1.5 channel, a sodium channel in the gastrointestinal smooth muscle and pacemaker cells, and thereby disrupts bowel function.

Specifically, SCN5A encodes the α subunit of the voltage-gated Na+channel Nav1.5. Because many patients with cardiac arrhythmias caused by mutations in SCN5A affecting pacemaker cells also have IBS symptoms, the investigators sought to determine whether some patients with IBS have SCN5A variants affecting Nav1.5 function.

Genotype analysis of the sodium channel in 584 patients with IBS and 1380 control subjects showed a defect in the SCN5A gene in 2.2% of the IBS patients compared with none of the control subjects. Mutant forms of SCN5A were expressed in HEK-293 cells, and voltage clamp analysis allowed evaluation of sodium channel function.

"About 2% of IBS patients carry mutations in SCN5A," the authors write. "Most of these are loss-of-function mutations that disrupt Na+ channel function. These findings provide a new pathogenic mechanism for IBS and possible treatment options."

Mutations Linked to Sodium Channel Function, IBS Symptoms

A genome-wide association study identified an IBS association signal for the SCN5A gene, which was replicated in 4 independent cohorts of patients with IBS and control patients (total, 1745 participants).

Although diarrhea-predominant IBS was the most prevalent form of IBS, occurring in 25% of the overall study population, constipation-predominant IBS (IBS-C) was significantly more prevalent among individuals with SCN5A mutations. IBS-C occurred in 31% of persons with SCN5A mutations, whereas diarrhea-predominant IBS occurred in only 10% (P < .05).

Electrophysiologic analysis of voltage-clamp experiments showed that 10 of 13 detected SCN5A mutations were associated with abnormal Nav1.5 function, including 9 with loss of sodium channel function and 1 with gain of sodium channel function.

The greatest effect in reducing NaV1.5 function occurred with the p.A997T-NaV1.5 mutation. When cells with this mutation were incubated with the drug mexiletine, sodium current was restored.

Giving mexiletine to a patient with IBS-C and this variant of the SCN5A mutation not only restored the function of the sodium channel but also abolished the patient's constipation and abdominal pain.

"In the dawn of the personalized medicine era we are discovering that for genetically complex diseases such as IBS there may be cohorts of patients with well-defined genetic abnormalities," the authors conclude. "Ion channels are directly involved in the mechanisms of visceral pain and [gastrointestinal] motility, therefore ion channelopathies may be involved in pathogenesis of IBS. For the first time we provide the direct molecular and functional evidence for functionally significant SCN5A mutations in a subset of IBS patients."

The National Institutes of Health, the Mayo Clinic Center for Cell Signaling in Gastroenterology, the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program, and the Swedish Research Council supported this study. One coauthor has reported serving as a consultant for Boston Scientific, Medtronic, and St. Jude Medical and receiving royalties or other funds from Transgenomic. Dr. Farrugia and the other authors have disclosed no relevant financial relationships.

Gastroenterology. Published online March 10, 2014. Abstract

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