Cystic fibrosis transmembrane conductance regulator

Cystic fibrosis transmembrane conductance regulator (CFTR) is a is_associated_with::membrane protein in vertebrates that is encoded by the CFTR is_associated_with::gene.

CFTR is an is_associated_with::ABC transporter-class is_associated_with::ion channel that codes for a protein that conducts is_associated_with::chloride and is_associated_with::thiocyanate ions across epithelial is_associated_with::cell membranes. Mutations of the CFTR gene affecting chloride ion channel function lead to dysregulation of epithelial fluid transport in the lung, pancreas and other organs, resulting in is_associated_with::cystic fibrosis. Complications include thickened mucus in the lungs with frequent respiratory infections, and pancreatic insufficiency giving rise to malnutrition and diabetes. These conditions lead to chronic disability and reduced life expectancy. In male patients, the progressive obstruction and destruction of the developing is_associated_with::vas deferens and epididymis appear to result from abnormal intraluminal secretions, causing is_associated_with::congenital absence of the vas deferens and male infertility.

Gene
The gene that encodes the human CFTR protein is found on chromosome 7, on the long arm at position q31.2. from is_associated_with::base pair 116,907,253 to base pair 117,095,955. CFTR is_associated_with::orthologs occur in the jawed vertebrates.

The CFTR gene has been used in animals as a is_associated_with::nuclear DNA phylogenetic marker. Large genomic sequences of this gene have been used to explore the is_associated_with::phylogeny of the major groups of is_associated_with::mammals, and confirmed the grouping of is_associated_with::placental orders into four major clades: is_associated_with::Xenarthra, is_associated_with::Afrotheria, is_associated_with::Laurasiatheria, and is_associated_with::Euarchonta plus is_associated_with::Glires.

Mutations
Nearly two thousand cystic fibrosis-causing is_associated_with::mutations have been described. The most common mutation, is_associated_with::ΔF508 results from a deletion (Δ) of three nucleotides which results in a loss of the amino acid is_associated_with::phenylalanine (F) at the 508th position on the protein. As a result the protein does not fold normally and is more quickly degraded. The vast majority of mutations are infrequent. The distribution and frequency of mutations varies among different populations which has implications for genetic screening and counseling.

Mutations consist of replacements, duplications, deletions or shortenings in the CFTR gene. This may result in proteins that may not function, work less effectively, are more quickly degraded, or are present in inadequate numbers.

It has been hypothesized that mutations in the CFTR gene may confer a selective advantage to heterozygous individuals. Cells expressing a mutant form of the CFTR protein are resistant to invasion by the Salmonella typhi bacterium, the agent of is_associated_with::typhoid fever, and mice carrying a single copy of mutant CFTR are resistant to diarrhea caused by cholera toxin.

List of common mutations
The most common mutations among caucasians are:
 * is_associated_with::ΔF508
 * G542X
 * G551D
 * N1303K
 * W1282X

Structure
The CFTR gene is approximately 189 kb in length, with 27 is_associated_with::exons and 26 is_associated_with::introns. CFTR is a is_associated_with::glycoprotein with 1480 is_associated_with::amino acids. The protein consists of five domains. There are two transmembrane domains, each with six spans of alpha helices. These are each connected to a nucleotide binding domain (NBD) in the cytoplasm. The first NBD is connected to the second transmembrane domain by a regulatory "R" domain that is a unique feature of CFTR, not present in other ABC transporters. The ion channel only opens when its R-domain has been phosphorylated by PKA and ATP is bound at the NBDs. The carboxyl terminal of the protein is anchored to the is_associated_with::cytoskeleton by a PDZ-interacting domain.

Location and function
CFTR functions as an ATP-gated is_associated_with::anion channel, increasing the conductance for certain is_associated_with::anions (e.g. Cl−) to flow down their is_associated_with::electrochemical gradient. ATP-driven is_associated_with::conformational changes in CFTR open and close a gate to allow transmembrane flow of anions down their is_associated_with::electrochemical gradient. This in contrast to other is_associated_with::ABC proteins, in which ATP-driven conformational changes fuel uphill substrate transport across cellular membranes. Essentially, CFTR is an ion channel that evolved as a 'broken' is_associated_with::ABC transporter that leaks when in open conformation.

The CFTR is found in the epithelial cells of many organs including the is_associated_with::lung, is_associated_with::liver, is_associated_with::pancreas, digestive tract, is_associated_with::reproductive tract, and is_associated_with::skin. Normally, the protein moves is_associated_with::chloride and is_associated_with::thiocyanate is_associated_with::ions (with a negative charge) out of an epithelial cell to the covering is_associated_with::mucus. Positively charged sodium ions follow passively, increasing the total is_associated_with::electrolyte concentration in the mucus, resulting in the movement of water out of cell by is_associated_with::osmosis.

In epithelial cells with motile cilia lining the bronchus and the oviduct, CFTR is located on cell membrane but not on cilia. In contrast to CFTR, is_associated_with::ENaC is located along the entire length of the cilia. These findings contradict a previous hypothesis that CFTR normally downregulates ENaC by direct interaction and that in CF patients, CFTR cannot downregulate ENaC causing hyper-absorption in the lungs and recurrent lung infections.

In is_associated_with::sweat glands, CFTR defects result in reduced transport of sodium chloride and sodium is_associated_with::thiocyanate in the reabsorptive duct and saltier sweat. This was the basis of a clinically important is_associated_with::sweat test for is_associated_with::cystic fibrosis before genetic screening was available.

Interactions
Cystic fibrosis transmembrane conductance regulator has been shown to interact with:


 * is_associated_with::DNAJC5,
 * is_associated_with::GOPC,
 * is_associated_with::PDZK1,
 * is_associated_with::PRKCE,
 * is_associated_with::SLC4A8,
 * is_associated_with::SNAP23,
 * SLC9A3R1,
 * SLC9A3R2, and
 * is_associated_with::STX1A,

It is inhibited by the anti-diarrhoea drug is_associated_with::crofelemer.

Related conditions

 * is_associated_with::Congenital bilateral absence of vas deferens: Males with congenital bilateral absence of the is_associated_with::vas deferens most often have a mild is_associated_with::mutation (a change that allows partial function of the gene) in one copy of the CFTR gene and a cystic fibrosis-causing mutation in the other copy of CFTR.


 * is_associated_with::Cystic fibrosis: More than 1,800 mutations in the CFTR gene have been found but the majority of these have not been associated with cystic fibrosis. Most of these mutations either substitute one is_associated_with::amino acid (a building block of proteins) for another amino acid in the CFTR protein or delete a small amount of is_associated_with::DNA in the CFTR gene. The most common mutation, called is_associated_with::ΔF508, is a deletion (Δ) of one amino acid (phenylalanine) at position 508 in the CFTR protein. This altered protein never reaches the cell membrane because it is degraded shortly after it is made. All disease-causing mutations in the CFTR gene prevent the channel from functioning properly, leading to a blockage of the movement of salt and water into and out of cells. As a result of this blockage, cells that line the passageways of the lungs, pancreas, and other organs produce abnormally thick, sticky mucus. This mucus obstructs the airways and glands, causing the characteristic signs and symptoms of cystic fibrosis. In addition, only thin mucus can be removed by cilia; thick mucus cannot, so it traps bacteria that give rise to chronic infections.


 * is_associated_with::Cholera: The CFTR channel is up-regulated by cholera toxin-mediated ADP-ribosylation, resulting in increased production of cAMP, which leads to oversecretion of Cl−. Na+ and H2O follow Cl− into the small intestine, resulting in dehydration and loss of electrolytes.