Cystic fibrosis transmembrane conductance regulator
Cystic fibrosis transmembrane conductance regulator 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 CF.
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 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 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 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 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 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 primarily known as a processing mutation which results from a deletion of three nucleotides which results in a loss of the amino acid phenylalanine 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 | Variant protein name | Variant legacy name | rsID | # alleles in CFTR2 | Allele frequency in CFTR2 | % pancreatic insufficient | Variant final determination |
| c.1521_1523delCTT | p.Phe508del | F508del | rs113993960 | 99061 | 0.69744 | 98% | CF-causing |
| c.1624G>T | p.Gly542X | G542X | rs113993959 | 3610 | 0.02542 | 98% | CF-causing |
| c.1652G>A | p.Gly551Asp | G551D | rs75527207 | 2986 | 0.02102 | 96% | CF-causing |
| c.3909C>G | p.Asn1303Lys | N1303K | rs80034486 | 2246 | 0.01581 | 98% | CF-causing |
| c.350G>A | p.Arg117His | R117H | rs78655421 | 1854 | 0.01305 | 23% | Varying clinical consequence |
| c.3846G>A | p.Trp1282X | W1282X | rs77010898 | 1726 | 0.01215 | 99% | CF-causing |
| c.489+1G>T | No protein name | 621+1G->T | rs78756941 | 1323 | 0.00931 | 99% | CF-causing |
| c.1657C>T | p.Arg553X | R553X | rs74597325 | 1323 | 0.00931 | 97% | CF-causing |
| c.1585-1G>A | No protein name | 1717-1G->A | rs76713772 | 1216 | 0.00856 | 97% | CF-causing |
| c.3718-2477C>T | No protein name | 3849+10kbC->T | rs75039782 | 1158 | 0.00815 | 33% | CF-causing |
| c.2657+5G>A | No protein name | 2789+5G->A | rs80224560 | 1027 | 0.00723 | 43% | CF-causing |
| c.1519_1521delATC | p. Ile507del | I507del | rs121908745 | 651 | 0.00458 | 98% | CF-causing |
| c.3484C>T | p.Arg1162X | R1162X | rs74767530 | 651 | 0.00458 | 97% | CF-causing |
| c.254G>A | p.Gly85Glu | G85E | rs75961395 | 616 | 0.00434 | 85% | CF-causing |
| c.3454G>C | p.Asp1152His | D1152H | rs75541969 | 571 | 0.00402 | 24% | Varying clinical consequence |
| c.2051_2052delAAinsG | p. Lys684SerfsX38 | 2183AA->G | rs121908799 | 542 | 0.00382 | 96% | CF-causing |
| c.3528delC | p. Lys1177SerfsX15 | 3659delC | rs121908747 | 539 | 0.00379 | 99% | CF-causing |
| c.1040G>C | p.Arg347Pro | R347P | rs77932196 | 533 | 0.00375 | 68% | CF-causing |
| c.1210−12T | No protein name | 5T | rs1805177 | 516 | 0.00363 | 28% | Varying clinical consequence |
| c.2988+1G>A | No protein name | 3120+1G->A | rs75096551 | 501 | 0.00353 | 98% | CF-causing |
| c.1364C>A | p.Ala455Glu | A455E | rs74551128 | 500 | 0.00352 | 34% | CF-causing |
| c.3140-26A>G | No protein name | 3272-26A->G | rs76151804 | 470 | 0.00331 | 29% | CF-causing |
| c.1000C>T | p.Arg334Trp | R334W | rs121909011 | 429 | 0.00302 | 40% | CF-causing |
| c.1766+1G>A | No protein name | 1898+1G->A | rs121908748 | 421 | 0.00296 | 99% | CF-causing |
| c.54-5940_273+10250del21kb | p.Ser18ArgfsX16 | CFTRdele2,3 | not found | 417 | 0.00294 | 100% | CF-causing |
| c.1679G>C | p.Arg560Thr | R560T | rs80055610 | 343 | 0.00241 | 98% | CF-causing |
| c.617T>G | p. Leu206Trp | L206W | rs121908752 | 333 | 0.00234 | 20% | CF-causing |
| c.2052dupA | p.Gln685ThrfsX4 | 2184insA | rs121908786 | 329 | 0.00232 | 85% | CF-causing |
| c.262_263delTT | p. Leu88IlefsX22 | 394delTT | rs121908769 | 307 | 0.00216 | 97% | CF-causing |
| c.178G>T | p.Glu60X | E60X | rs77284892 | 296 | 0.00208 | 99% | CF-causing |
| c.1477C>T | p.Gln493X | Q493X | rs77101217 | 292 | 0.00206 | 98% | CF-causing |
| c.579+1G>T | No protein name | 711+1G->T | rs77188391 | 274 | 0.00193 | 98% | CF-causing |
| c.2052delA | p. Lys684AsnfsX38 | 2184delA | rs121908746 | 255 | 0.00180 | 98% | CF-causing |
| c.200C>T | p.Pro67Leu | P67L | rs368505753 | 239 | 0.00168 | 34% | CF-causing |
| c.3302T>A | p.Met1101Lys | M1101K | rs36210737 | 238 | 0.00168 | 69% | CF-causing |
| c.1408A>G | p.Met470Val | M470V | rs213950 | 235 | 0.00165 | 46% | Non CF-causing |
| c.3276C>A or c.3276C>G | p.Tyr1092X | Y1092X | rs121908761 | 225 | 0.00158 | 98% | CF-causing |
| c.3196C>T | p.Arg1066Cys | R1066C | rs78194216 | 220 | 0.00155 | 98% | CF-causing |
| c.1021_1022dupTC | p.Phe342HisfsX28 | 1154insTC | rs387906360 | 214 | 0.00151 | 99% | CF-causing |
| c.3773dupT | p. Leu1258PhefsX7 | 3905insT | rs121908789 | 210 | 0.00148 | 97% | CF-causing |
| c.1646G>A | p.Ser549Asn | S549N | rs121908755 | 203 | 0.00143 | 84% | CF-causing |
| c.1040G>A | p.Arg347His | R347H | rs77932196 | 199 | 0.00140 | 24% | CF-causing |
| c.948delT | p.Phe316LeufsX12 | 1078delT | rs121908744 | 184 | 0.00130 | 99% | CF-causing |
| c.1210-33_1210-6GTT | No protein name | 5T;TG12 | not found | 182 | 0.00128 | 14% | Varying clinical consequence |
| c.3472C>T | p.Arg1158X | R1158X | rs79850223 | 179 | 0.00126 | 99% | CF-causing |
| c.2834C>T | p.Ser945Leu | S945L | rs397508442 | 167 | 0.00118 | 40% | CF-causing |
| c.1558G>T | p. Val520Phe | V520F | rs77646904 | 156 | 0.00110 | 98% | CF-causing |
| c.443T>C | p. Ile148Thr | I148T | rs35516286 | 148 | 0.00104 | 88% | Non CF-causing |
| c.349C>T | p.Arg117Cys | R117C | rs77834169 | 146 | 0.00103 | 24% | CF-causing |