Cystic fibrosis transmembrane conductance regulator (F508del mutation) (CFTR (F508del))

The F508del-mutated Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) is the most prevalent genetic variant responsible for cystic fibrosis, affecting approximately 70-90% of patients [1, 3, 6]. This mutation involves the deletion of a single phenylalanine residue at position 508, which leads to a multi-faceted defect in protein biogenesis and function [1, 4]. Primarily, it causes a Class II processing defect where the protein misfolds in the endoplasmic reticulum and is targeted for proteasomal degradation, preventing its translocation to the apical membrane of epithelial cells [2, 5, 10]. Even when small amounts of the mutant protein reach the cell surface, they exhibit defective channel gating (Class III) and reduced stability (Class VI) [5, 14]. As a cAMP-regulated anion channel, its absence or dysfunction disrupts the transport of chloride and bicarbonate ions, leading to the accumulation of thick, viscous mucus in the respiratory and gastrointestinal tracts [3, 9, 10]. Pharmacological management utilizes CFTR modulators, including "correctors" like elexacaftor and tezacaftor that assist in protein folding and trafficking, and "potentiators" like ivacaftor that increase the channel's open probability [10, 13, 14].

Other names

F508del CFTRDeltaF508 CFTRΔF508 CFTRPhe508del CFTRCFTR-ΔF508

CFTR correctors facilitate the proper folding and trafficking of the misfolded F508del protein to the cell surface, while CFTR potentiators increase the gating frequency and open probability of the channel once it is localized at the plasma membrane [10, 11, 14].