Abstract
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[Cl–]; 87–105 mEq/L). A database review of 25 individuals with F312del and a CF-causing variant revealed elevated sw[Cl–] (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 (CFBE41o–) 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.
| Original language | English |
|---|---|
| Article number | e148841 |
| Pages (from-to) | 1-15 |
| Journal | JCI Insight |
| Volume | 7 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - 22 Mar 2022 |
Bibliographical note
Funding Information:We wish to thank the individuals who underwent rigorous evaluation and contributed their tissue samples and clinical data to this study, as well as the patients, caregivers, and families at CF centers for their contributions to patient registry databases. This work was supported by NIH grant R01DK44003 (to GRC); CF Foundation grants CUTTIN13A1, CUTTIN5XX0, and CUTTIN16IO (to GRC), GORALS19Y5 (to JLG), Bridge18XX0 (to RJB), and SHARMA19I0 (to NS); and CF Foundation Therapeutics grant SHEPPA14XX0 (to DNS).
Funding Information:
grants from Cystic Fibrosis Foundation Therapeutics during the conduct of the study and a grant from the Vertex Innovation Award from Vertex Pharmaceuticals (European). NS reports grants from the Vertex Research Innovation Award from Vertex Pharmaceuticals. GRC reports grants from the US CF Foundation and National Institute of Diabetes and Digestive and Kidney Diseases.
Publisher Copyright:
© 2022, Raraigh et al.