Abstract

The SCN5A-encoded voltage-gated mechanosensitive sodium (Na+) channel NaV1.5 is expressed in human GI smooth muscle cells and interstitial cells of Cajal. NaV1.5 contributes to smooth muscle electrical slow waves and mechanical sensitivity. In predominately Caucasian IBS patient cohorts, 2-3% have SCN5A missense mutations which alter NaV1.5 function and may contribute to IBS pathophysiology. In this study examined a racially and ethnically diverse cohort of IBS patients for SCN5A missense mutations, and compared them to IBS negative controls, and determined the resulting NaV1.5 voltage-dependent and mechanosensitive properties. All SCN5A exons were sequenced from somatic DNA of 252 Rome III IBS patients with diverse ethnic and racial backgrounds. Missense mutations were introduced into wild-type SCN5A by site-directed mutagenesis and co-transfected with GFP into HEK-293 cells. NaV1.5 voltage-dependent and mechanosensitive functions were studied by whole cell electrophysiology with and without shear force. Five of 252 IBS patients (2.0%) had six rare SCN5A mutations, which were absent in 377 IBS-negative controls. All (6/6, 100%) IBS-associated NaV1.5 mutations had voltage-dependent gating abnormalities: current density reduction (R225W, R433C, R986Q, F1293S) and altered voltage dependence (R225W, R433C, R986Q, G1037V, F1293S) and at least one kinetic parameter was altered in all mutations. Four IBS-associated SCN5A mutations (4/6, 67%) resulted in altered NaV1.5 mechanosensitivity (R225W, R433C, R986Q, F1293S). In this racially and ethnically diverse cohort of IBS patients we show that 2% of IBS patients harbor SCN5A mutations that are absent in IBS-negative controls and result in NaV1.5 channels with abnormal voltage-dependent and mechanosensitive function.

View details for DOI 10.1152/ajpgi.00016.2017

View details for PubMedID 29167113