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Cystic fibrosis transmembrane conductance regulator

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Title: Cystic fibrosis transmembrane conductance regulator  
Author: World Heritage Encyclopedia
Language: English
Subject: Epithelial sodium channel, Membrane transport protein, Transporter Classification Database, Sweat test, Cystic fibrosis
Collection: Abc Transporters, Cystic Fibrosis, Mutated Genes
Publisher: World Heritage Encyclopedia

Cystic fibrosis transmembrane conductance regulator

Cystic fibrosis transmembrane conductance regulator (ATP-binding cassette sub-family C, member 7)
NBD1 of human CFTR complexed with ATP. PDB rendering based on .
Available structures
PDB Ortholog search: PDBe, RCSB
Symbols  ; ABC35; ABCC7; CF; CFTR/MRP; MRP7; TNR-CFTR; dJ760C5.1
External IDs IUPHAR: ChEMBL: GeneCards:
EC number
Species Human Mouse
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)
PubMed search

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 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,[5] causing congenital absence of the vas deferens and male infertility.


  • Gene 1
    • Mutations 1.1
    • List of common mutations 1.2
  • Structure 2
  • Location and function 3
    • Interactions 3.1
  • Related conditions 4
  • References 5
  • Further reading 6
  • External links 7


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.


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


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 cell by osmosis.

In epithelial cells with motile cilia lining the bronchus and the oviduct, CFTR is located on cell membrane but not on cilia. In contrast to CFTR, ENaC is located along the entire length of the cilia.[17] These findings contradict a previous hypothesis that CFTR normally downregulates ENaC by direct interaction and that in CF patients, CFTR cannot downregulate ENaC causing hyper-absorption in the lungs and recurrent lung infections.

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


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

It is inhibited by the anti-diarrhoea drug crofelemer.

Related conditions

  • cilia; thick mucus cannot, so it traps bacteria that give rise to chronic infections.
  • Cholera: The CFTR channel is up-regulated by cholera toxin-mediated ADP-ribosylation, resulting in increased production of cAMP, which leads to oversecretion of Cl. Na+ and H2O follow Cl into the small intestine, resulting in dehydration and loss of electrolytes.


  1. ^ a b Gadsby DC, Vergani P, Csanády L (2006). "The ABC protein turned chloride channel whose failure causes cystic fibrosis". Nature 440 (7083): 477–83.  
  2. ^ a b Rommens JM, Iannuzzi MC, Kerem B, Drumm ML, Melmer G, Dean M, Rozmahel R, Cole JL, Kennedy D, Hidaka N (September 1989). "Identification of the cystic fibrosis gene: chromosome walking and jumping". Science 245 (4922): 1059–65.  
  3. ^ Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R, Grzelczak Z, Zielenski J, Lok S, Plavsic N, Chou JL (1989). "Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA". Science 245 (4922): 1066–73.  
  4. ^ Childers M, Eckel G, Himmel A, Caldwell J (2007). "A new model of cystic fibrosis pathology: lack of transport of glutathione and its thiocyanate conjugates". Med. Hypotheses 68 (1): 101–12.  
  5. ^ Marcorelles P, Gillet D, Friocourt G, Ledé F, Samaison L, Huguen G, Ferec C (March 2012). "Cystic fibrosis transmembrane conductance regulator protein expression in the male excretory duct system during development". Hum. Pathol. 43 (3): 390–7.  
  6. ^ a b "OrthoMaM phylogenetic marker: CFTR coding sequence". 
  7. ^ Davies, R; Conroy, S-J; Davies, WL; Potter, IC; Rrezise, Ann EO (19–23 June 2005). "Evolution and Regulation of the Cystic Fibrosis Gene" (conference paper). Molecular Biology and Evolution (MBE05) Conference. Retrieved 28 July 2014. 
  8. ^ Prasad AB, Allard MW, Green ED (2008). "Confirming the phylogeny of mammals by use of large comparative sequence data sets". Mol. Biol. Evol. 25 (9): 1795–808.  
  9. ^ "Cystic Fibrosis Mutation Database: Statistics". Cystic Fibrosis Centre at the Hospital for Sick Children in Toronto. Retrieved 28 July 2014. 
  10. ^ Rowe SM, Miller S, Sorscher EJ (May 2005). "Cystic fibrosis". N. Engl. J. Med. 352 (19): 1992–2001.  
  11. ^ Kavic SM, Frehm EJ, Segal AS (1999). "Case studies in cholera: lessons in medical history and science". Yale J Biol Med 72 (6): 393–408.  
  12. ^ Araújo FG, Novaes FC, Santos NP, Martins VC, Souza SM, Santos SE, Ribeiro-dos-Santos AK (January 2005). "Prevalence of deltaF508, G551D, G542X, and R553X mutations among cystic fibrosis patients in the North of Brazil". Braz. J. Med. Biol. Res. 38 (1): 11–5.  
  13. ^ Cystic Fibrosis Mutation Database. "Genomic DNA sequence". 
  14. ^ Sheppard DN, Welsh MJ (January 1999). "Structure and function of the CFTR chloride channel". Physiol. Rev. 79 (1 Suppl): S23–45.  
  15. ^ a b Short DB, Trotter KW, Reczek D, Kreda SM, Bretscher A, Boucher RC, Stutts MJ, Milgram SL (July 1998). "An apical PDZ protein anchors the cystic fibrosis transmembrane conductance regulator to the cytoskeleton". J. Biol. Chem. 273 (31): 19797–801.  
  16. ^ Moskwa P, Lorentzen D, Excoffon KJ, Zabner J, McCray PB, Nauseef WM, Dupuy C, Bánfi B (January 2007). "A novel host defense system of airways is defective in cystic fibrosis". Am. J. Respir. Crit. Care Med. 175 (2): 174–83.  
  17. ^ Enuka Y, Hanukoglu I, Edelheit O, Vaknine H, Hanukoglu A (2012). "Epithelial sodium channels (ENaC) are uniformly distributed on motile cilia in the oviduct and the respiratory airways". Histochem. Cell Biol. 137 (3): 339–53.  
  18. ^ Xu Y, Szép S, Lu Z (2009). "The antioxidant role of thiocyanate in the pathogenesis of cystic fibrosis and other inflammation-related diseases". Proc. Natl. Acad. Sci. U.S.A. 106 (48): 20515–9.  
  19. ^ Yonei Y, Tanaka M, Ozawa Y, Miyazaki K, Tsukada N, Inada S, Inagaki Y, Miyamoto K, Suzuki O, Okawa H (April 1992). "Primary hepatocellular carcinoma with severe hypoglycemia: involvement of insulin-like growth factors". Liver 12 (2): 90–3.  
  20. ^ Zhang H, Peters KW, Sun F, Marino CR, Lang J, Burgoyne RD, Frizzell RA (2002). "Cysteine string protein interacts with and modulates the maturation of the cystic fibrosis transmembrane conductance regulator". J. Biol. Chem. 277 (32): 28948–58.  
  21. ^ Cheng J, Moyer BD, Milewski M, Loffing J, Ikeda M, Mickle JE, Cutting GR, Li M, Stanton BA, Guggino WB (2002). "A Golgi-associated PDZ domain protein modulates cystic fibrosis transmembrane regulator plasma membrane expression". J. Biol. Chem. 277 (5): 3520–9.  
  22. ^ a b c Gentzsch M, Cui L, Mengos A, Chang XB, Chen JH, Riordan JR (2003). "The PDZ-binding chloride channel ClC-3B localizes to the Golgi and associates with cystic fibrosis transmembrane conductance regulator-interacting PDZ proteins". J. Biol. Chem. 278 (8): 6440–9.  
  23. ^ Wang S, Yue H, Derin RB, Guggino WB, Li M (2000). "Accessory protein facilitated CFTR-CFTR interaction, a molecular mechanism to potentiate the chloride channel activity". Cell 103 (1): 169–79.  
  24. ^ Liedtke CM, Yun CH, Kyle N, Wang D (2002). "Protein kinase C epsilon-dependent regulation of cystic fibrosis transmembrane regulator involves binding to a receptor for activated C kinase (RACK1) and RACK1 binding to Na+/H+ exchange regulatory factor". J. Biol. Chem. 277 (25): 22925–33.  
  25. ^ a b Park M, Ko SB, Choi JY, Muallem G, Thomas PJ, Pushkin A, Lee MS, Kim JY, Lee MG, Muallem S, Kurtz I (2002). "The cystic fibrosis transmembrane conductance regulator interacts with and regulates the activity of the HCO3- salvage transporter human Na+-HCO3- cotransport isoform 3". J. Biol. Chem. 277 (52): 50503–9.  
  26. ^ a b Cormet-Boyaka E, Di A, Chang SY, Naren AP, Tousson A, Nelson DJ, Kirk KL (2002). "CFTR chloride channels are regulated by a SNAP-23/syntaxin 1A complex". Proc. Natl. Acad. Sci. U.S.A. 99 (19): 12477–82.  
  27. ^ Hegedüs T, Sessler T, Scott R, Thelin W, Bakos E, Váradi A, Szabó K, Homolya L, Milgram SL, Sarkadi B (2003). "C-terminal phosphorylation of MRP2 modulates its interaction with PDZ proteins". Biochem. Biophys. Res. Commun. 302 (3): 454–61.  
  28. ^ Wang S, Raab RW, Schatz PJ, Guggino WB, Li M (1998). "Peptide binding consensus of the NHE-RF-PDZ1 domain matches the C-terminal sequence of cystic fibrosis transmembrane conductance regulator (CFTR)". FEBS Lett. 427 (1): 103–8.  
  29. ^ Moyer BD, Duhaime M, Shaw C, Denton J, Reynolds D, Karlson KH, Pfeiffer J, Wang S, Mickle JE, Milewski M, Cutting GR, Guggino WB, Li M, Stanton BA (2000). "The PDZ-interacting domain of cystic fibrosis transmembrane conductance regulator is required for functional expression in the apical plasma membrane". J. Biol. Chem. 275 (35): 27069–74.  
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  31. ^ Sun F, Hug MJ, Lewarchik CM, Yun CH, Bradbury NA, Frizzell RA (2000). "E3KARP mediates the association of ezrin and protein kinase A with the cystic fibrosis transmembrane conductance regulator in airway cells". J. Biol. Chem. 275 (38): 29539–46.  
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  33. ^ The Clinical and Functional TRanslation of CFTR (CFTR2); available at , accessed 2013-12-12

Further reading

  • Kulczycki LL, Kostuch M, Bellanti JA (2003). "A clinical perspective of cystic fibrosis and new genetic findings: relationship of CFTR mutations to genotype-phenotype manifestations". Am. J. Med. Genet. A 116A (3): 262–7.  
  • Vankeerberghen A, Cuppens H, Cassiman JJ (2002). "The cystic fibrosis transmembrane conductance regulator: an intriguing protein with pleiotropic functions". J. Cyst. Fibros. 1 (1): 13–29.  
  • 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". Hum. Mutat. 1 (3): 197–203.  
  • McIntosh I, Cutting GR (1992). "Cystic fibrosis transmembrane conductance regulator and the etiology and pathogenesis of cystic fibrosis". FASEB J. 6 (10): 2775–82.  
  • Drumm ML, Collins FS (1993). "Molecular biology of cystic fibrosis". Mol. Genet. Med. 3: 33–68.  
  • Kerem B, Kerem E (1996). "The molecular basis for disease variability in cystic fibrosis". Eur. J. Hum. Genet. 4 (2): 65–73.  
  • Devidas S, Guggino WB (1997). "CFTR: domains, structure, and function". J. Bioenerg. Biomembr. 29 (5): 443–51.  
  • Nagel G (1999). "Differential function of the two nucleotide binding domains on cystic fibrosis transmembrane conductance regulator". Biochim. Biophys. Acta 1461 (2): 263–74.  
  • Boyle MP (2000). "Unique presentations and chronic complications in adult cystic fibrosis: do they teach us anything about CFTR?". Respir. Res. 1 (3): 133–5.  
  • Greger R, Schreiber R, Mall M, Wissner A, Hopf A, Briel M, Bleich M, Warth R, Kunzelmann K (2001). "Cystic fibrosis and CFTR". Pflugers Arch. 443 Suppl 1: S3–7.  
  • Bradbury NA (2001). "cAMP signaling cascades and CFTR: is there more to learn?". Pflugers Arch. 443 Suppl 1: S85–91.  
  • Dahan D, Evagelidis A, Hanrahan JW, Hinkson DA, Jia Y, Luo J, Zhu T (2001). "Regulation of the CFTR channel by phosphorylation". Pflugers Arch. 443 Suppl 1: S92–6.  
  • Cohn JA, Noone PG, Jowell PS (2002). "Idiopathic pancreatitis related to CFTR: complex inheritance and identification of a modifier gene". J. Investig. Med. 50 (5): 247S–255S.  
  • Schwartz M (2003). "[Cystic fibrosis transmembrane conductance regulator (CFTR) gene: mutations and clinical phenotypes]". Ugeskr. Laeg. 165 (9): 912–6.  
  • Wong LJ, Alper OM, Wang BT, Lee MH, Lo SY (2003). "Two novel null mutations in a Taiwanese cystic fibrosis patient and a survey of East Asian CFTR mutations". Am. J. Med. Genet. A 120A (2): 296–8.  
  • Cuppens H, Cassiman JJ (2004). "CFTR mutations and polymorphisms in male infertility". Int. J. Androl. 27 (5): 251–6.  
  • Cohn JA, Mitchell RM, Jowell PS (2005). "The impact of cystic fibrosis and PSTI/SPINK1 gene mutations on susceptibility to chronic pancreatitis". Clin. Lab. Med. 25 (1): 79–100.  
  • Southern KW, Peckham D (2004). "Establishing a diagnosis of cystic fibrosis". Chron Respir Dis 1 (4): 205–10.  
  • Kandula L, Whitcomb DC, Lowe ME (2006). "Genetic issues in pediatric pancreatitis". Curr Gastroenterol Rep 8 (3): 248–53.  
  • Marcet B, Boeynaems JM (2006). "Relationships between cystic fibrosis transmembrane conductance regulator, extracellular nucleotides and cystic fibrosis". Pharmacol. Ther. 112 (3): 719–32.  
  • Wilschanski M, Durie PR (2007). "Patterns of GI disease in adulthood associated with mutations in the CFTR gene". Gut 56 (8): 1153–63.  

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)
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