Cystic Fibrosis: Channeling the Discovery of CFTR Mutations

Cystic fibrosis (CF) is an autosomal recessive disease caused by mutation of the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR is a protein forming chloride channels in the membrane of epithelial cells. It consists of two transmembrane domains (TMD), two nucleotide binding domains (NBD), and an R domain. The channel is first activated by the phosphorylation of its R domain. ATP then binds to CFTR’s NBDs for the channel to conduct Cl- out of the cell. Mutations in CFTR can cause misfolding and prevent adequate transportation of Cl-. The most common cause of the disease is the deletion of phenylalanine 508 of CFTR. When ∆F508 reaches the ER, it is recognized as irreparable and thus targeted for degradation, which causes the symptoms of CF. The third most common mutation, G551D, does not function properly at the membrane. Molecular chaperones such as Hdj-2/Hsc70, Hsp90, and HspBP1 may rescue CFTR misfolding. This has therapeutic value because once ∆F508 is sent to the membrane, it can function normally. There are many treatments for CF, including airway clearing techniques, antibiotics, and lung transplantation. Recent research has suggested that oligonucleotide insertion, curcumin treatment, and digotoxin treatment can reverse the ∆F508 phenotype