Cystic fibrosis transmembrane conductance regulator
Ensembl | |||||||||
---|---|---|---|---|---|---|---|---|---|
UniProt | |||||||||
RefSeq (mRNA) | |||||||||
RefSeq (protein) | |||||||||
Location (UCSC) | Chr 7: 117.29 – 117.72 Mb | Chr 6: 18.17 – 18.32 Mb | |||||||
PubMed search | [3] | [4] |
View/Edit Human | View/Edit Mouse |
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
Gene
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
Mutations
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]
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_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[5] | 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_1210-6GT[12]T[4] | 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 |
DeltaF508
DeltaF508 (ΔF508), full name CFTRΔF508 or F508del-CFTR (rs113993960), is a specific mutation within the CFTR gene involving
Effects
This section needs more primary sources. (March 2019) |
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
Having a
Being a
Mechanism
The CFTR gene is located on the long arm of chromosome 7, at position q31.2, and ultimately codes for a sequence of 1,480 amino acids. Normally, the three
Prevalence
ΔF508 is present on at least one copy of chromosome 7 in approximately one in 30
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
Location and function
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
In the airways of the lung, CFTR is most highly expressed by rare specialized cells called
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
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000001626 - Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000041301 - Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ PMID 30516439.
- ^ PMID 2772657.
- ^ "Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Gene | The Embryo Project Encyclopedia". embryo.asu.edu. Retrieved 2022-09-26.
- S2CID 84566748.
- PMID 21840567.
- S2CID 19335113.
- ^ a b "OrthoMaM phylogenetic marker: CFTR coding sequence". Archived from the original on 2016-03-02. Retrieved 2010-03-12.
- ^ Davies R, Conroy SJ, Davies WL, Potter IC, Trezise AE (19–23 June 2005). "Evolution and Regulation of the Cystic Fibrosis Gene" (conference paper). Molecular Biology and Evolution (MBE05) Conference. Retrieved 28 July 2014.
- ^ "Genetics and CF". The Cystic Fibrosis Center at Stanford (in Samoan). Retrieved 2022-10-23.
- PMID 18453548.
- ^ "The Clinical and Functional TRanslation of CFTR (CFTR2): CFTR2 Variant List History". US CF Foundation, Johns Hopkins University, Cystic Fibrosis Centre at the Hospital for Sick Children in Toronto. Retrieved 2 August 2017.[permanent dead link]
- PMID 28881097.
- PMID 33683511.
- PMID 15888700.
- PMID 11138935.
- ^ "CFTR2". Retrieved 2021-07-08.
- PMID 12007216.
- PMID 12475759.
- ^ "Cystic Fibrosis Research Directions". National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).
- PMID 22664493. Archived from the original(PDF) on 2020-03-12. Retrieved 2019-03-16.
- ^ CCDS Report for Consensus CDS: Report for CCDS5773.1 (current version) NCBI
- PMID 20628052.
- ^ "Re: Is there a connection between cystic fibrosis and cholera?".
- S2CID 5894247.
- PMID 11344348.
- S2CID 22970136.
- PMID 15781764.
- ^ ECFS Annual Report: What It Means to the UK Archived 2018-05-01 at the Wayback Machine Cystic Fibrosis Trust
- S2CID 38005421.
- ^ Cystic Fibrosis Mutation Database. "Genomic DNA sequence". Archived from the original on 2016-08-22. Retrieved 2013-04-06.
- ^ a b "CFTR". Johns Hopkins Cystic Fibrosis Center. Retrieved 2022-10-09.
- PMID 9922375.
- ^ PMID 30459277.
- S2CID 5361509.
- PMID 9922375.
- ^ PMID 9677412.
- S2CID 4383918.
- ^ S2CID 15178940.
- S2CID 3761720.
- S2CID 58026884.
- ^ "CF Study Finds New Cells Called Ionocytes Carrying High levels of CFTR Gene". Cystic Fibrosis News Today. 3 August 2018.
- PMID 30069044.
- PMID 30069046.
- ^ S2CID 8504408.
- PMID 17082494.
- PMID 19918082.
- PMID 1320177.
- PMID 12039948.
- PMID 11707463.
- ^ PMID 12471024.
- S2CID 16697781.
- PMID 11956211.
- ^ PMID 12403779.
- ^ PMID 12209004.
- PMID 12615054.
- S2CID 20803242.
- PMID 10852925.
- PMID 9671706.
- PMID 10893422.
- S2CID 4395005.
- PMID 26857764.
- PMID 27053340.
- PMID 22850599.
- S2CID 23344660.
- PMID 23616952.
- ^ "Phase 3 Study of VX-770 Shows Marked Improvement in Lung Function Among People with Cystic Fibrosis with G551D Mutation". Press Release. Cystic Fibrosis Foundation. 2011-02-23.
- ^ Herper M (27 December 2012). "The Most Important New Drug Of 2012". Forbes.
- ^ Nocera J (18 July 2014). "The $300,000 Drug". The New York Times.
Further reading
- Kulczycki LL, Kostuch M, Bellanti JA (January 2003). "A clinical perspective of cystic fibrosis and new genetic findings: relationship of CFTR mutations to genotype-phenotype manifestations". American Journal of Medical Genetics. Part A. 116A (3): 262–267. S2CID 9245855.
- Vankeerberghen A, Cuppens H, Cassiman JJ (March 2002). "The cystic fibrosis transmembrane conductance regulator: an intriguing protein with pleiotropic functions". Journal of Cystic Fibrosis. 1 (1): 13–29. PMID 15463806.
- Tsui LC (1992). "Mutations and sequence variations detected in the cystic fibrosis transmembrane conductance regulator (CFTR) gene: a report from the Cystic Fibrosis Genetic Analysis Consortium". Human Mutation. 1 (3): 197–203. S2CID 35904538.
- McIntosh I, Cutting GR (July 1992). "Cystic fibrosis transmembrane conductance regulator and the etiology and pathogenesis of cystic fibrosis". FASEB Journal. 6 (10): 2775–2782. S2CID 24932803.
- Drumm ML, Collins FS (1993). "Molecular biology of cystic fibrosis". Molecular Genetic Medicine. 3: 33–68. PMID 7693108.
- Kerem B, Kerem E (1996). "The molecular basis for disease variability in cystic fibrosis". European Journal of Human Genetics. 4 (2): 65–73. S2CID 41476164.
- Devidas S, Guggino WB (October 1997). "CFTR: domains, structure, and function". Journal of Bioenergetics and Biomembranes. 29 (5): 443–451. S2CID 6000695.
- Nagel G (December 1999). "Differential function of the two nucleotide binding domains on cystic fibrosis transmembrane conductance regulator". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1461 (2): 263–274. PMID 10581360.
- Boyle MP (2000). "Unique presentations and chronic complications in adult cystic fibrosis: do they teach us anything about CFTR?". Respiratory Research. 1 (3): 133–135. PMID 11667976.
- Greger R, Schreiber R, Mall M, Wissner A, Hopf A, Briel M, et al. (2001). "Cystic fibrosis and CFTR". Pflügers Archiv. 443 (Suppl 1): S3–S7. S2CID 8057614.
- Bradbury NA (2001). "cAMP signaling cascades and CFTR: is there more to learn?". Pflügers Archiv. 443 (Suppl 1): S85–S91. S2CID 19373036.
- Dahan D, Evagelidis A, Hanrahan JW, Hinkson DA, Jia Y, Luo J, Zhu T (2001). "Regulation of the CFTR channel by phosphorylation". Pflügers Archiv. 443 (Suppl 1): S92–S96. S2CID 8144727.
- Cohn JA, Noone PG, Jowell PS (September 2002). "Idiopathic pancreatitis related to CFTR: complex inheritance and identification of a modifier gene". Journal of Investigative Medicine. 50 (5): 247S–255S. S2CID 34017638.
- Schwartz M (February 2003). "[Cystic fibrosis transmembrane conductance regulator (CFTR) gene: mutations and clinical phenotypes]". Ugeskrift for Laeger. 165 (9): 912–916. PMID 12661515.
- Wong LJ, Alper OM, Wang BT, Lee MH, Lo SY (July 2003). "Two novel null mutations in a Taiwanese cystic fibrosis patient and a survey of East Asian CFTR mutations". American Journal of Medical Genetics. Part A. 120A (2): 296–298. S2CID 41060230.
- Cuppens H, Cassiman JJ (October 2004). "CFTR mutations and polymorphisms in male infertility". International Journal of Andrology. 27 (5): 251–256. PMID 15379964.
- Cohn JA, Mitchell RM, Jowell PS (March 2005). "The impact of cystic fibrosis and PSTI/SPINK1 gene mutations on susceptibility to chronic pancreatitis". Clinics in Laboratory Medicine. 25 (1): 79–100. PMID 15749233.
- Southern KW, Peckham D (2004). "Establishing a diagnosis of cystic fibrosis". Chronic Respiratory Disease. 1 (4): 205–210. PMID 16281647.
- Kandula L, Whitcomb DC, Lowe ME (June 2006). "Genetic issues in pediatric pancreatitis". Current Gastroenterology Reports. 8 (3): 248–253. S2CID 23606613.
- Marcet B, Boeynaems JM (December 2006). "Relationships between cystic fibrosis transmembrane conductance regulator, extracellular nucleotides and cystic fibrosis". Pharmacology & Therapeutics. 112 (3): 719–732. PMID 16828872.
- Wilschanski M, Durie PR (August 2007). "Patterns of GI disease in adulthood associated with mutations in the CFTR gene". Gut. 56 (8): 1153–1163. PMID 17446304.
External links
- GeneReviews/NCBI/NIH/UW entry on CFTR-Related Disorders - Cystic Fibrosis (CF, Mucoviscidosis) and Congenital Absence of the Vas Deferens (CAVD)
- The Cystic Fibrosis Transmembrane Conductance Regulator Protein
- The Human Gene Mutation Database - CFTR Records
- Cystic Fibrosis Mutation Database
- Oak Ridge National Laboratory CFTR Information
- CFTR at OMIM (National Center for Biotechnology Information)
- Overview of all the structural information available in the PDB for UniProt: P13569 (Human Cystic fibrosis transmembrane conductance regulator) at the PDBe-KB.
- Overview of all the structural information available in the PDB for UniProt: P26361 (Mouse Cystic fibrosis transmembrane conductance regulator) at the PDBe-KB.