Cystic fibrosis transmembrane conductance regulator 1230676 224257266 2008-07-08T00:58:44Z ProteinBoxBot 3991663 Replaced protein Box Template with PBB Template for easy viewing. {{PBB|geneid=1080}} '''Cystic fibrosis transmembrane conductance regulator''' ('''CFTR''') is an [[ABC transporter]]-class [[protein]] and [[ion channel]] that transports [[chloride]] ions across epithelial [[cell membrane]]s. Mutations of the CFTR gene affect functioning of the chloride ion channels in these cell membranes, leading to [[cystic fibrosis]] and [[congenital absence of the vas deferens]]. ==Structure== The gene that encodes for [[CFTR (gene)|CFTR]] is found on the [[human]] [[chromosome 7 (human)|chromosome 7]], on the long arm at position q31.2. It contains about 170,000 [[base pair]]s. The encoded CFTR is a [[glycoprotein]] with 1480 [[amino acid]]s. The protein consists of five domains. There are two transmembrane domains, each with six spans of [[Alpha helix|alpha helices]]. These are each connected to a [[nucleotide binding fold]] (NBF) in the cytoplasm. These two nucleotide binding folds are linked to a single regulatory R-domain that is a unique feature belonging only to this type of ABC protein. The ion channel only opens when its R-domain has been phosphorylated by PKA and two molecules of [[Adenosine triphosphate|ATP]] have bound to the two NBFs.<ref>Sheppard DN, Welsh MJ. ''Structure and Function of the CFTR Chloride Channel.'' Physiol Rev. 1999 Jan;79(1 Supple):S23-45. PMID 9922375</ref> The [[C-terminal end|carboxyl terminal]] of the protein is anchored to the [[cytoskeleton]] by a [[PDZ (biology)|PDZ]] domain interaction.<ref>Short DB, Trotter KW, Reczek D, Kreda SM, Bretscher A, Boucher RC, Stutts MJ, Milgram SL. ''An apical PDZ protein anchors the cystic fibrosis transmembrane conductance regulator to the cytoskeleton.'' J Biol Chem. 1998 Jul 31;273(31):19797-801. PMID 9677412</ref> ==Function== 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]] [[ion]]s (with a negative charge) out of an epithelial cell to the covering [[mucus]]. This results in an electrical gradient being formed and in the movement of (positively charged) sodium ions in the same direction as the chloride via a paracellular pathway. Due to this movement, the water potential of the mucus is reduced, resulting in the movement of water here by [[osmosis]] and a more fluid mucus. [[Image:CFTR.jpg|thumbnail|right|280px]] In [[sweat gland]]s, CFTR defects result in reduced transport of sodium chloride 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 ( see [http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=1320177 The Relevance of Sweat Testing for the Diagnosis of Cystic Fibrosis in the Genomic Era]). ==Mutations== Well over one thousand [[mutation]]s have been described that can affect the CFTR gene. Such mutations can cause two genetic disorders, [[congenital bilateral absence of vas deferens]] and the more widely known disorder [[cystic fibrosis]]. Both disorders arise from the blockage of the movement of ions and, therefore, water into and out of cells. In congenital bilateral absence of vas deferens, the protein may be still functional but not at normal efficiency, this leads to the production of thick [[mucus]], which blocks the developing [[vas deferens]]. In people with mutations giving rise to cystic fibrosis, the blockage in ion transport occurs in epithelial cells that line the passageways of the [[lungs]], [[pancreas]], and other organs. This leads to chronic dysfunction, disability, and a reduced life expectancy. 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 (508) position on the protein. As a result the protein does not [[Protein folding|fold]] normally and is more quickly degraded. The vast majority of mutations are quite rare. 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..<ref>Rowe SM, Miller S, Sorscher EJ. Cystic fibrosis. N Engl J Med. 2005 May 12;352(19):1992-2001. PMID 15888700 </ref> 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 typhii bacterium, the agent of typhoid fever, and mice carrying a single copy of mutant CFTR are resistant to diarrhea caused by cholera toxin. ==List of common mutations== The most common mutations in a Caucasian population are: <ref name="mutations">''Prevalence of ΔF508, G551D, G542X, R553X mutations among cystic fibrosis patients in the North of Brazil.'' Brazilian Journal of Medical and Biological Research 2005; 38:11-15. PMID 15665983</ref> * [[ΔF508]] * G542X * G551D * N1303K * W1282X ==References== {{reflist}} ==Further reading== {{refbegin | 2}} {{PBB_Further_reading | citations = *{{cite journal | author=Tsui LC |title=Mutations and sequence variations detected in the cystic fibrosis transmembrane conductance regulator (CFTR) gene: a report from the Cystic Fibrosis Genetic Analysis Consortium |journal=Hum. Mutat. |volume=1 |issue= 3 |pages= 197–203 |year= 1993 |pmid= 1284534 |doi= 10.1002/humu.1380010304 }} *{{cite journal | author=McIntosh I, Cutting GR |title=Cystic fibrosis transmembrane conductance regulator and the etiology and pathogenesis of cystic fibrosis |journal=FASEB J. |volume=6 |issue= 10 |pages= 2775–82 |year= 1992 |pmid= 1378801 |doi= }} *{{cite journal | author=Drumm ML, Collins FS |title=Molecular biology of cystic fibrosis |journal=Mol. Genet. Med. |volume=3 |issue= |pages= 33–68 |year= 1993 |pmid= 7693108 |doi= }} *{{cite journal | author=Kerem B, Kerem E |title=The molecular basis for disease variability in cystic fibrosis |journal=Eur. J. Hum. Genet. |volume=4 |issue= 2 |pages= 65–73 |year= 1996 |pmid= 8744024 |doi= }} *{{cite journal | author=Devidas S, Guggino WB |title=CFTR: domains, structure, and function |journal=J. Bioenerg. Biomembr. |volume=29 |issue= 5 |pages= 443–51 |year= 1998 |pmid= 9511929 |doi=10.1023/A:1022430906284 }} *{{cite journal | author=Nagel G |title=Differential function of the two nucleotide binding domains on cystic fibrosis transmembrane conductance regulator |journal=Biochim. Biophys. Acta |volume=1461 |issue= 2 |pages= 263–74 |year= 2000 |pmid= 10581360 |doi= }} *{{cite journal | author=Boyle MP |title=Unique presentations and chronic complications in adult cystic fibrosis: do they teach us anything about CFTR? |journal=Respir. Res. |volume=1 |issue= 3 |pages= 133–5 |year= 2003 |pmid= 11667976 |doi=10.1186/rr23 }} *{{cite journal | author=Greger R, Schreiber R, Mall M, ''et al.'' |title=Cystic fibrosis and CFTR |journal=Pflugers Arch. |volume=443 Suppl 1 |issue= |pages= S3–7 |year= 2002 |pmid= 11845294 |doi= 10.1007/s004240100635 }} *{{cite journal | author=Bradbury NA |title=cAMP signaling cascades and CFTR: is there more to learn? |journal=Pflugers Arch. |volume=443 Suppl 1 |issue= |pages= S85–91 |year= 2002 |pmid= 11845310 |doi= 10.1007/s004240100651 }} *{{cite journal | author=Dahan D, Evagelidis A, Hanrahan JW, ''et al.'' |title=Regulation of the CFTR channel by phosphorylation |journal=Pflugers Arch. |volume=443 Suppl 1 |issue= |pages= S92–6 |year= 2002 |pmid= 11845311 |doi= 10.1007/s004240100652 }} *{{cite journal | author=Cohn JA, Noone PG, Jowell PS |title=Idiopathic pancreatitis related to CFTR: complex inheritance and identification of a modifier gene |journal=J. Investig. Med. |volume=50 |issue= 5 |pages= 247S–255S |year= 2002 |pmid= 12227654 |doi= }} *{{cite journal | author=Kulczycki LL, Kostuch M, Bellanti JA |title=A clinical perspective of cystic fibrosis and new genetic findings: relationship of CFTR mutations to genotype-phenotype manifestations |journal=Am. J. Med. Genet. A |volume=116 |issue= 3 |pages= 262–7 |year= 2003 |pmid= 12503104 |doi= 10.1002/ajmg.a.10886 }} *{{cite journal | author=Schwartz M |title=[Cystic fibrosis transmembrane conductance regulator (CFTR) gene: mutations and clinical phenotypes] |journal=Ugeskr. Laeg. |volume=165 |issue= 9 |pages= 912–6 |year= 2003 |pmid= 12661515 |doi= }} *{{cite journal | author=Wong LJ, Alper OM, Wang BT, ''et al.'' |title=Two novel null mutations in a Taiwanese cystic fibrosis patient and a survey of East Asian CFTR mutations |journal=Am. J. Med. Genet. A |volume=120 |issue= 2 |pages= 296–8 |year= 2004 |pmid= 12833420 |doi= 10.1002/ajmg.a.20039 }} *{{cite journal | author=Cuppens, Harry; Cassiman, Jean- Jacques |title=CFTR mutations and polymorphisms in male infertility |journal=Int. J. Androl. |volume=27 |issue= 5 |pages= 251–6 |year= 2005 |pmid= 15379964 |doi= 10.1111/j.1365-2605.2004.00485.x }} *{{cite journal | author=Cohn JA, Mitchell RM, Jowell PS |title=The impact of cystic fibrosis and PSTI/SPINK1 gene mutations on susceptibility to chronic pancreatitis |journal=Clin. Lab. Med. |volume=25 |issue= 1 |pages= 79–100 |year= 2005 |pmid= 15749233 |doi= 10.1016/j.cll.2004.12.007 }} *{{cite journal | author=Southern KW, Peckham D |title=Establishing a diagnosis of cystic fibrosis |journal=Chronic respiratory disease |volume=1 |issue= 4 |pages= 205–10 |year= 2005 |pmid= 16281647 |doi=10.1191/1479972304cd044rs }} *{{cite journal | author=Kandula L, Whitcomb DC, Lowe ME |title=Genetic issues in pediatric pancreatitis |journal=Current gastroenterology reports |volume=8 |issue= 3 |pages= 248–53 |year= 2006 |pmid= 16764792 |doi= 10.1007/s11894-006-0083-8}} *{{cite journal | author=Marcet B, Boeynaems JM |title=Relationships between cystic fibrosis transmembrane conductance regulator, extracellular nucleotides and cystic fibrosis |journal=Pharmacol. Ther. |volume=112 |issue= 3 |pages= 719–32 |year= 2007 |pmid= 16828872 |doi= 10.1016/j.pharmthera.2006.05.010 }} *{{cite journal | author=Wilschanski M, Durie PR |title=Patterns of GI disease in adulthood associated with mutations in the CFTR gene |journal=Gut |volume=56 |issue= 8 |pages= 1153–63 |year= 2007 |pmid= 17446304 |doi= 10.1136/gut.2004.062786 }} }} {{refend}} ==External links== *[http://macromoleculeinsights.com/cftr.php The Cystic Fibrosis Transmembrane Conductance Regulator Protein] *[http://archive.uwcm.ac.uk/uwcm/mg/search/120584.html The Human Gene Mutation Database - CFTR Records] *[http://www.genet.sickkids.on.ca/cftr/ Cystic Fibrosis Mutation Database] *[http://www.ornl.gov/sci/techresources/Human_Genome/posters/chromosome/cftr.shtml Oak Ridge National Laboratory CFTR Information] *[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602421 CFTR at OMIM (National Center for Biotechnology Information)] {{Ion channels}} [[Category:Genes associated with genetic disorders]] [[Category:ABC transporters]] [[de:Cystic Fibrosis Transmembrane Conductance Regulator]] [[fr:Gène et protéine CFTR]] [[hu:CFTR]] [[sk:Cystic fibrosis transmembrane conductance regulator]] <!-- The PBB_Controls template provides controls for Protein Box Bot, please see Template:PBB_Controls for details. --> {{PBB_Controls | update_page = yes | require_manual_inspection = no | update_protein_box = yes | update_summary = no | update_citations = yes }}