1XMI, 1XMJ, 2BBO, 2BBS, 2BBT, 2LOB, 2PZE, 2PZF, 2PZG, 3GD7, 3ISW, 4WZ6, 5D2D, 5D3E, 5D3F108012638ENSG00000001626ENSMUSG00000041301P13569P26361NM_000492NM_021050NP_000483NP_066388Cystic fibrosis transmembrane conductance regulator (CFTСR) is a membrane protein and anion channel in vertebrates that is encoded by the CFTR gene.

Mutations of the CFTR gene affecting anion channel function lead to dysregulation of epithelial lining fluid (mucus) transport in the lung, pancreas and other organs, resulting in cystic fibrosis.

Complications include thickened mucus in the lungs with frequent respiratory infections, and pancreatic insufficiency giving rise to malnutrition and diabetes.

[19] Normally, the protein allows movement of chloride, bicarbonate and thiocyanate[20] ions (with a negative charge) out of an epithelial cell into the airway surface liquid and mucus.

Positively charged sodium ions follow passively, increasing the total electrolyte concentration in the mucus, resulting in the movement of water out of the cell via osmosis.

[24][failed verification] Each individual inherits two copies of the CFTR (cystic fibrosis transmembrane conductance regulator) gene.

[32] The most common mutations that cause cystic fibrosis and pancreatic insufficiency in humans are:[33] DeltaF508 (ΔF508), full name CFTRΔF508 or F508del-CFTR (rs113993960), is a specific mutation within the CFTR gene involving deletion of three nucleotides spanning codons for amino acid positions 507 and 508 of the CFTR gene on chromosome 7, which ultimately results in the loss of a single codon for the amino acid phenylalanine (F).

In organisms with two complements of the mutation, the protein is almost entirely absent from the cell membrane, and these critical ion transport functions are not performed.

[36] Having a homozygous pair of genes with the ΔF508 mutation prevents the CFTR protein from assuming its normal position in the cell membrane.

[37] Being a heterozygous carrier (having a single copy of ΔF508) results in decreased water loss during diarrhea because malfunctioning or absent CFTR proteins cannot maintain stable ion gradients across cell membranes.

For example, it has been shown that heterozygosity for cystic fibrosis is associated with increased airway reactivity, and heterozygotes may be at risk for poor pulmonary function.

Heterozygotes with wheeze have been shown to be at higher risk for poor pulmonary function or development and progression of chronic obstructive lung disease.

[38] The CFTR gene is located on the long arm of chromosome 7, at position q31.2, and ultimately codes for a sequence of 1,480 amino acids.

[41] Another theory posits that CF carriers (heterozygotes for ΔF508) are more resistant to typhoid fever, since CFTR has been shown to act as a receptor for Salmonella typhi bacteria to enter intestinal epithelial cells.

[45] Approximately 50% of cystic fibrosis cases in Europe are due to homozygous ΔF508 mutations (this varies widely by region),[46] while the allele frequency of ΔF508 is about 70%.

ATP-driven conformational changes in CFTR open and close a gate to allow the transmembrane flow of anions down their electrochemical gradient.

[5] This in contrast to other ABC proteins, in which ATP-driven conformational changes fuel uphill substrate transport across cellular membranes.

Other members of the ABC transporter superfamily are involved in the uptake of nutrients in prokaryotes, or in the export of a variety of substrates in eukaryotes.

ABC transporters have evolved to transduce the free energy of ATP hydrolysis to the uphill movement of substrates across the cell membrane.

ATP binds to each nucleotide-binding domain, which results in the subsequent NBD dimerization, leading to the rearrangement of the transmembrane helices.

In particular, NBD dimerization (favored by ATP binding) is coupled to transition to an outward-facing conformation in which an open transmembrane pathway for anions is formed.

Ivacaftor (brand name Kalydeco, developed as VX-770) is a medication approved by the FDA in 2012, for people with cystic fibrosis who have specific CFTR mutations.

[74][75] Ivacaftor was developed by Vertex Pharmaceuticals in conjunction with the Cystic Fibrosis Foundation and is the first medication that treats the underlying cause rather than the symptoms of the disease.