WS06.2 R117H-CFTR has a defect in channel gating activity that can be potentiated by ivacaftor

Background The R117H mutation is associated with residual chloride transport and a delayed onset of CF symptoms. Although generally called a conductance mutation, R117H-CFTR exhibits defective channel gating. This study aimed to more fully explore the mechanistic defect of R117H-CFTR and to evaluate the effect of ivacaftor, a CFTR potentiator, on R117H-CFTR. Methods and Results In single-channel, patch-clamp studies, the channel open probability (gating activity) of R117H-CFTR was 22% of normal, whereas the channel conductance was 88% of normal. The channel gating activity of R117H-CFTR was characterized by frequent but brief openings of the channel compared with normal CFTR. The brief openings are consistent with a low channel open probability due in part to destabilization of the channel open state by R117H. The addition of ivacaftor increased the channel open probability of R117H-CFTR from 22% to 42% of normal. The increase in open probability was due to an increase in the frequency of channel opening and a decreased closed duration. Channel open duration and conductance were not increased. In Ussing chamber studies using R117H-5T/F508del-human bronchial epithelial cells from two donor bronchi, chloride transport was 23% of normal, which is consistent with residual chloride transport. Ivacaftor treatment for 18–24 hours increased chloride transport to 36% of normal. Conclusion These data confirm that R117H is a residual function CFTR mutation that causes a predominant defect in channel gating activity that is potentiated by ivacaftor. Based on these in vitro data, ivacaftor would be expected to enhance CFTR activity in people with the R117H mutation.