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

Geneticist Lap-Chee Tsui and his team identified the CFTR gene in 1989 as the gene linked with cystic fibrosis.

The CFTR gene codes for an ABC transporter-class ion channel protein that conducts chloride and bicarbonate ions across epithelial cell membranes. 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. 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, causing congenital absence of the vas deferens and male infertility, and found associated with an imbalance of fatty acids.

Tissue and intracellular localization

The CFTR is found in the epithelial cells of many organs including the lung, liver, pancreas, digestive tract, and the female reproductive tract and male reproductive tract including the testis, Sertoli cells, spermatozoa. epididymis, and the vas deferens.

In the airways of the lung, CFTR is most highly expressed by rare specialized cells called pulmonary ionocytes. In the skin, CFTR is strongly expressed in the sebaceous and eccrine sweat glands. In the eccrine glands, CFTR is located on the apical membrane of the epithelial cells that make up the duct of these sweat glands.

Normally, the protein allows movement of chloride, bicarbonate and thiocyanate 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 contrast, ENaC (Epithelial sodium channel) is located along the entire length of the cilia.

In sweat glands, defective CFTR results in reduced transport of sodium chloride and sodium thiocyanate 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.

Gene

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

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.

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

Mutations Nearly 1000 cystic fibrosis-causing mutations have been described. 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. 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.

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

The most common mutations that cause cystic fibrosis and pancreatic insufficiency in humans are: Variant cDNA name (ordered 5' to 3') Variant protein name Variant legacy name rsID # alleles in CFTR2 Allele frequency in CFTR2 % pancreatic insufficient Variant final determination (July 2020) c.1521_1523delCTTp.Phe508delF508delrs113993960990610.6974498%CF-causing c.1624G>Tp.Gly542XG542Xrs11399395936100.0254298%CF-causing c.1652G>Ap.Gly551AspG551Drs7552720729860.0210296%CF-causing c.3909C>Gp.Asn1303LysN1303Krs8003448622460.0158198%CF-causing c.350G>Ap.Arg117HisR117Hrs7865542118540.0130523%Varying clinical consequence c.3846G>Ap.Trp1282XW1282Xrs7701089817260.0121599%CF-causing c.489+1G>TNo protein name621+1G->Trs7875694113230.0093199%CF-causing c.1657C>Tp.Arg553XR553Xrs7459732513230.0093197%CF-causing c.1585-1G>ANo protein name1717-1G->Ars7671377212160.0085697%CF-causing c.3718-2477C>TNo protein name3849+10kbC->Trs7503978211580.0081533%CF-causing c.2657+5G>ANo protein name2789+5G->Ars8022456010270.0072343%CF-causing c.1519_1521delATCp. Ile507delI507delrs1219087456510.0045898%CF-causing c.3484C>Tp.Arg1162XR1162Xrs747675306510.0045897%CF-causing c.254G>Ap.Gly85GluG85Ers759613956160.0043485%CF-causing c.3454G>Cp.Asp1152HisD1152Hrs755419695710.0040224%Varying clinical consequence c.2051_2052delAAinsGp. Lys684SerfsX382183AA->Grs1219087995420.0038296%CF-causing c.3528delCp. Lys1177SerfsX153659delCrs1219087475390.0037999%CF-causing c.1040G>Cp.Arg347ProR347Prs779321965330.0037568%CF-causing c.1210−12TNo protein name5Trs18051775160.0036328%Varying clinical consequence c.2988+1G>ANo protein name3120+1G->Ars750965515010.0035398%CF-causing c.1364C>Ap.Ala455GluA455Ers745511285000.0035234%CF-causing c.3140-26A>GNo protein name3272-26A->Grs761518044700.0033129%CF-causing c.1000C>Tp.Arg334TrpR334Wrs1219090114290.0030240%CF-causing c.1766+1G>ANo protein name1898+1G->Ars1219087484210.0029699%CF-causing c.54-5940_273+10250del21kbp.Ser18ArgfsX16CFTRdele2,3not found4170.00294100%CF-causing c.1679G>Cp.Arg560ThrR560Trs800556103430.0024198%CF-causing c.617T>Gp. Leu206TrpL206Wrs1219087523330.0023420%CF-causing c.2052dupAp.Gln685ThrfsX42184insArs1219087863290.0023285%CF-causing c.262_263delTTp. Leu88IlefsX22 394delTTrs1219087693070.0021697%CF-causing c.178G>Tp.Glu60XE60Xrs772848922960.0020899%CF-causing c.1477C>Tp.Gln493XQ493Xrs771012172920.0020698%CF-causing c.579+1G>TNo protein name711+1G->Trs771883912740.0019398%CF-causing c.2052delAp. Lys684AsnfsX382184delArs1219087462550.0018098%CF-causing c.200C>Tp.Pro67LeuP67Lrs3685057532390.0016834%CF-causing c.3302T>Ap.Met1101LysM1101Krs362107372380.0016869%CF-causing c.1408A>Gp.Met470ValM470Vrs2139502350.0016546%Non CF-causing c.3276C>A or c.3276C>Gp.Tyr1092XY1092Xrs1219087612250.0015898%CF-causing c.3196C>Tp.Arg1066CysR1066Crs781942162200.0015598%CF-causing c.1021_1022dupTCp.Phe342HisfsX281154insTCrs3879063602140.0015199%CF-causing c.3773dupTp. Leu1258PhefsX73905insTrs1219087892100.0014897%CF-causing c.1646G>Ap.Ser549AsnS549Nrs1219087552030.0014384%CF-causing c.1040G>Ap.Arg347HisR347Hrs779321961990.0014024%CF-causing c.948delTp.Phe316LeufsX121078delTrs1219087441840.0013099%CF-causing c.1210-33_1210-6GTTNo protein name5T;TG12not found1820.0012814%Varying clinical consequence c.3472C>Tp.Arg1158XR1158Xrs798502231790.0012699%CF-causing c.2834C>Tp.Ser945LeuS945Lrs3975084421670.0011840%CF-causing c.1558G>Tp. Val520PheV520Frs776469041560.0011098%CF-causing c.443T>Cp. Ile148ThrI148Trs355162861480.0010488%Non CF-causing c.349C>Tp.Arg117CysR117Crs778341691460.0010324%CF-causing

DeltaF508 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). A person with the CFTRΔF508 mutation will produce an abnormal CFTR protein that lacks this phenylalanine residue and which cannot fold properly. Most of this mutated protein does not escape the endoplasmic reticulum for further processing. The small amounts that reach the plasma membrane are destabilized and the anion channel opens infrequently. Having two copies of this mutation (one inherited from each parent) is by far the most common cause of cystic fibrosis (CF), responsible for nearly two-thirds of mutations worldwide.

Effects

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 chloride and bicarbonate ions out of cells; it also simultaneously inhibits the uptake of sodium ions by another channel protein. Both of these functions help to maintain an ion gradient that causes osmosis to draw water out of the cells. The ΔF508 mutation leads to the misfolding of CFTR and its eventual degradation in the ER. 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.

Having a homozygous pair of genes with the ΔF508 mutation prevents the CFTR protein from assuming its normal position in the cell membrane. This causes increased water retention in cells, corresponding dehydration of the extracellular space, and an associated cascade of effects on various parts of the body. These effects include: thicker mucous membranes in the epithelia of afflicted organs; obstruction of narrow respiratory airways as a result of thicker mucus and inhibition of the free movement of muco cilia; congenital absence of the vas deferens due to increased mucus thickness during fetal development; pancreatic insufficiency due to blockage of the pancreatic duct with mucus; and increased risk of respiratory infection due to build-up of thick, nutrient-rich mucus where bacteria thrive. Mucus thickening is also hypothesized to disrupt innate immune-system mechanisms due to changes in immune-cell and molecular profiles (including decreased alveolar macrophage activity and increased cytokine and neutrophil presence). This results in an aggravated systemic inflammatory response and impaired phagocytosis, reducing the body's ability to fight infection. These are the symptoms of cystic fibrosis, a genetic disorder; however, ΔF508 is not the only mutation that causes this disorder.