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Cystic fibrosis transmembrane conductance regulator

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Template:PBB Cystic fibrosis transmembrane conductance regulator (CFTR) is a membrane protein and chloride channel in vertebrates that is encoded by the CFTR gene.[1][2]

CFTR is an ABC transporter-class ion channel that codes for a protein that conducts chloride[3] and thiocyanate[4] ions across epithelial 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 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 vas deferens (spermatic cord) and epididymis appear to result from abnormal intraluminal secretions,[5] causing congenital absence of the vas deferens and male infertility.

Gene

The location of the CFTR gene on chromosome 7

The gene that encodes the human CFTR protein is found on chromosome 7, on the long arm at position q31.2.[2] from base pair 116,907,253 to base pair 117,095,955. CFTR orthologs [6] occur in the jawed vertebrates.[7]

The CFTR gene has been used in animals as a nuclear DNA phylogenetic marker.[6] Large genomic sequences of this gene have been used to explore the phylogeny of the major groups of mammals,[8] and confirmed the grouping of placental orders into four major clades: Xenarthra, Afrotheria, Laurasiatheria, and Euarchonta plus Glires.

Mutations

Nearly two thousand cystic fibrosis-causing mutations have been described.[9] The most common mutation, ΔF508 results from a deletion (Δ) of three nucleotides which results in a loss of the amino acid 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.[10]

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 typhoid fever, and mice carrying a single copy of mutant CFTR are resistant to diarrhea caused by cholera toxin.[11]

List of common mutations

The most common mutations among caucasians are:[12]

  • ΔF508
  • G542X
  • G551D
  • N1303K
  • W1282X

Structure

The CFTR gene is approximately 189 kb in length, with 27 exons and 26 introns.[13] CFTR is a glycoprotein with 1480 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.[14] The carboxyl terminal of the protein is anchored to the cytoskeleton by a PDZ-interacting domain.[15]

Location and function

The CFTR protein is a channel protein that controls the flow of H2O and Cl− ions in and out of cells inside the lungs. When the CFTR protein is working correctly, as shown in Panel 1, ions freely flow in and out of the cells. However, when the CFTR protein is malfunctioning as in Panel 2, these ions cannot flow out of the cell due to a blocked channel. This causes cystic fibrosis, characterized by the buildup of thick mucus in the lungs.

CFTR functions as an ATP-gated anion channel, increasing the conductance for certain anions (e.g. Cl−) to flow down their electrochemical gradient. ATP-driven conformational changes in CFTR open and close a gate to allow transmembrane flow of anions down their electrochemical gradient.[1] This in contrast to other 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' ABC transporter that leaks when in open conformation.

The CFTR is found in the epithelial cells of many organs including the lung, liver, pancreas, digestive tract, reproductive tract, and skin. Normally, the protein moves chloride and thiocyanate[16] ions (with a negative charge) out of an epithelial cell to the covering 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.

In epithelial cells with motile cilia lining the bronchus and the oviduct, CFTR is located on the cell membrane but not on cilia. In contrast, ENaC (Epithelial sodium channel) is located along the entire length of the cilia.[17]

In sweat glands, defective CFTR results in reduced transport of sodium chloride and sodium thiocyanate[18] in the reabsorptive duct and therefore saltier sweat. This was the basis of a clinically important sweat test for cystic fibrosis before genetic screening was available.[19]

Interactions

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

It is inhibited by the anti-diarrhoea drug crofelemer.

  • Congenital bilateral absence of vas deferens: Males with congenital bilateral absence of the vas deferens most often have a mild 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.
  • Cystic fibrosis: More than 1,800 mutations in the CFTR gene have been found[33] but the majority of these have not been associated with cystic fibrosis.[citation needed] Most of these mutations either substitute one amino acid (a building block of proteins) for another amino acid in the CFTR protein or delete a small amount of DNA in the CFTR gene. The most common mutation, called 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.
  • Cholera: ADP-ribosylation caused by cholera toxin results in increased production of cyclic AMP which in turn opens the CFTR channel which leads to oversecretion of Cl−. Na+ and H2O follow Cl− into the small intestine, resulting in dehydration and loss of electrolytes.[34]

Drug target

CFTR has been a drug target in efforts to find treatments for related conditions. Ivacaftor (trade name Kalydeco, developed as VX-770) is a drug approved by the FDA in 2012 for people with cystic fibrosis who have specific CFTR mutations[35][36] Ivacaftor was developed by Vertex Pharmaceuticals in conjunction with the Cystic Fibrosis Foundation and is the first drug that treats the underlying cause rather than the symptoms of the disease.[37] Called "the most important new drug of 2012",[38] and "a wonder drug"[39] it is one of the most expensive drugs, costing over US$300,000 per year, which has led to criticism of Vertex for the high cost.

References

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Further reading

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