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).
Dr Michael Ackerman and colleagues from Minnesota, USA investigated whether patients with IBS have SCN5A variants that affect the function of NaV1.5.
The team performed genotype analysis of SCN5A in 584 persons with IBS and 1380 without IBS.
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.
The research team found missense mutations in SCN5A in 2% of patients.
|Missense mutations in SCN5A were found in 2% of patients|
Diarrhea-predominant IBS was the most prevalent form of IBS in the overall study population.
However, the team noted that a greater percentage of individuals with SCN5A mutations had constipation-predominant IBS than diarrhea-predominant IBS.
Electrophysiologic analysis showed that 10 of 13 detected mutations disrupted NaV1.5 function.
The team observed that the 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 normalized their bowel habits.
In the genome-wide association study and 4 replicated studies, the SCN5A locus was strongly associated with IBS.
Dr Ackerman and team commented, "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."