CFTR bearing variant p.Phe312del exhibits function inconsistent with phenotype and negligible response to ivacaftor

The chloride channel dysfunction caused by deleterious cystic fibrosis transmembrane conductance regulator (CFTR) variants generally correlates with severity of cystic fibrosis (CF). However, 3 adults bearing the common severe variant p.Phe508del (legacy: F508del) and a deletion variant in an ivacaftor binding region of CFTR (p.Phe312del; legacy: F312del) manifested only elevated sweat chloride concentration (sw[CI-]; 87-105 mEq/L). A database review of 25 individuals with F312del and a CF-causing variant revealed elevated sw[CI-] (75-123 mEq/L) and variable CF features. F312del occurs at a higher-than-expected frequency in the general population, confirming that individuals with F312del and a CF-causing variant do not consistently develop overt CF features. In primary nasal cells, CFTR bearing F312del and F508del generated substantial chloride transport (66.0% +/- 4.5% of WT-CFTR) but did not respond to ivacaftor. Single-channel analysis demonstrated that F312del did not affect current flow through CFTR, minimally altered gating, and ablated the ivacaftor response. When expressed stably in CF bronchial epithelial (CFBE410(-)) cells, F312del-CFTR demonstrated residual function (50.9% +/- 3.3% WT-CFTR) and a subtle decrease in forskolin response compared with WT-CFTR. F312del provides an exception to the established correlation between CFTR chloride transport and CF phenotype and informs our molecular understanding of ivacaftor response.

Automated summary

The presence of specific CFTR variants can cause dysfunction in chloride channels, which is generally associated with the severity of cystic fibrosis. However, some individuals with these variants do not consistently display overt cystic fibrosis features. A study found that a certain variant, F312del, occurs at a higher-than-expected frequency in the general population, suggesting that individuals with this variant and a CF-causing variant may not develop typical cystic fibrosis features. This finding provides additional insight into the molecular understanding of the response to ivacaftor.