Cystic fibrosis transmembrane conductance regulator

Cystic fibrosis transmembrane conductance regulator (CFTR) is a

Geneticist Lap-Chee Tsui and his team identified the CFTR gene in 1989 as the gene linked with CF (cystic fibrosis).^[7]

The CFTR gene codes for an

The gene that encodes the human CFTR protein is found on

Each individual inherits two copies of the CFTR (cystic fibrosis transmembrane conductance regulator) gene. However, some of the inherited copies have been altered. So far, the CFTR gene has been associated with over 700 distinct mutations. An individual with CF inherits two defective copies of the CFTR gene. These mutations might be heterozygous, meaning they include two different mutations, and homozygous, meaning they involve the same mutation. Delta F508 is the most common mutation, accounting for more than 70% of all mutations. Those who are homozygous for Delta F508 are commonly affected by pancreatic insufficiency.[13]

The CFTR gene has been used in animals as a

Nearly 1000 cystic fibrosis-causing mutations have been described.^[15] The most common mutation, DeltaF508 (ΔF508) primarily known as a processing mutation which 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.^[16] 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.

Drug discovery for therapeutics to address CF in all patients is complicated due to a large number of disease-causing mutations. Ideally, a library of cell lines and cell-based assays corresponding to all mutants is required to screen for broadly-active drug candidates. Cell engineering methods including fluorogenic oligonucleotide signaling probes may be used to detect and isolate clonal cell lines for each mutant.^[17]

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.^[18]

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.^[19]

The most common mutations that cause cystic fibrosis and pancreatic insufficiency in humans are:^[20]

DeltaF508

DeltaF508 (ΔF508), full name CFTRΔF508 or F508del-CFTR (rs113993960), is a specific mutation within the CFTR gene involving

Effects

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The CFTR protein is largely expressed in cells of the pancreas, intestinal and respiratory epithelia, and all exocrine glands. When properly folded, it is shuttled to the cell membrane, where it becomes a transmembrane protein that forms aqueous channels allowing the flow of

Cystic fibrosis ΔF508 heterozygotes may be overrepresented among individuals with asthma and may have poorer lung function than non-carriers.^[29][30] Carriers of a single CF mutation have a higher prevalence of chronic rhinosinusitis than the general population.^[31] Approximately 50% of cystic fibrosis cases in Europe are due to homozygous ΔF508 mutations (this varies widely by region),^[32] while the allele frequency of ΔF508 is about 70%.^[33] The remaining cases are caused by over 1,500 other mutations, including R117H, 1717-1G>A, and 2789+56G>A. These mutations, when combined with each other or even a single copy of ΔF508, may cause CF symptoms. The genotype is not strongly correlated with severity of the CF, though specific symptoms have been linked to certain mutations.

Structure

The CFTR gene is approximately 189

The CFTR gene is made up of 27 exons that encode its gene makeup and is found on the long (q) arm of chromosome 7 at locus 31.2. Exons are DNA fragments that provide the code for a protein structure.

CFTRs consist of five domains including two trans-membrane domains, each linked to a nucleotide-binding domain. CFTR also contains another domain called the regulatory domain. 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. They have two main conformations, one where the cargo binding site is facing the cytosol or inward facing (ATP free), and one where it is outward facing (ATP bound). ATP binds to each nucleotide-binding domain, which results in the subsequent NBD dimerization, leading to the rearrangement of the transmembrane helices. This changes the accessibility of the cargo binding site from an inward-facing position to an outward facing one. ATP binding, and the hydrolysis that follows, drives the alternative exposure of the cargo binding site, ensuring a unidirectional transport of cargo against an electrochemical gradient. In CFTR, alternating between an inward-facing conformation to an outward-facing one results in channel gating. 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.^[41] Subsequent hydrolysis (at the canonical active site, site 2, including Walker motifs of NBD2) destabilizes the NBD dimer and favors return to the inward-facing conformation, in which the anion permeation pathway is closed off.^[5]

The CFTR is found in the epithelial cells of many organs including the

Normally, the protein allows movement of chloride, bicarbonate and thiocyanate^[49] 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.

In epithelial cells with motile cilia lining the bronchus and the oviduct, CFTR is located on the apical cell membrane but not on cilia.

In sweat glands, defective CFTR results in reduced transport of sodium chloride and sodium thiocyanate^[50] in the resorptive duct and therefore saltier sweat. This is the basis of a clinically important sweat test for cystic fibrosis often used diagnostically with genetic screening.^[51]

Interactions

Cystic fibrosis transmembrane conductance regulator has been shown to

It is inhibited by the anti-diarrhoea drug crofelemer.

Related conditions

• 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^[65] but the majority of these have not been associated with cystic fibrosis.^[66] 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 Over secretion of Cl⁻. Na⁺ and H₂O follow Cl⁻ into the small intestine, resulting in dehydration and loss of electrolytes.^[67]

Drug target

CFTR has been a