Cystic fibrosis transmembrane conductance regulator

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 1xmi.
Symbols CFTR; ABC35; ABCC7; CF; CFTR/MRP; MRP7; TNR-CFTR; dJ760C5.1
External IDs OMIM602421 MGI88388 HomoloGene55465 GeneCards: CFTR Gene
EC number
Species Human Mouse
Entrez 1080 12638
Ensembl ENSG00000001626 ENSMUSG00000041301
UniProt P13569 Q8CC89
RefSeq (mRNA) NM_000492.3 NM_021050.2
RefSeq (protein) NP_000483.3 NP_066388.1
Location (UCSC) Chr 7:
117.12 – 117.31 Mb
Chr 6:
18.12 – 18.27 Mb
PubMed search [1] [2]

Cystic fibrosis transmembrane conductance regulator (CFTR) is a protein[1] that in humans is encoded by the CFTR gene.[2]

CFTR is a ABC transporter-class ion channel that transports chloride and thiocyanate[3] ions across epithelial cell membranes. 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.



The location of the CFTR gene on chromosome 7

The gene that encodes the CFTR protein is found on the human 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 [4] have also been identified in all mammals for which complete genome data are available.

The CFTR gene has been used in animals as a nuclear DNA phylogenetic marker.[4] Large genomic sequences of this gene have been used to explore the phylogeny of the major groups of mammals,[5] and confirmed the grouping of placental orders into four major clades: Xenarthra, Afrotheria, Laurasiatheria, and Euarchonta plus Glires.


Well over one thousand mutations 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 position on the protein. As a result the protein does not 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.[6]

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.[citation needed]

List of common mutations


The most common mutations among caucasians are:[7]

  • ΔF508
  • G542X
  • G551D
  • N1303K
  • W1282X


The CFTR gene is approximately 189 kb in length. This gene encodes the instruction to build the CFTR protein. 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.[8] The carboxyl terminal of the protein is anchored to the cytoskeleton by a PDZ-interacting domain.[9]


CFTR functions as a cAMP-activated ATP-gated anion channel, increasing the conductance for certain anions (e.g. Cl) to flow down their electrochemical gradient. ATP-driven conformational changes, which in other ABC proteins fuel uphill substrate transport across cellular membranes, in CFTR open and close a gate to allow transmembrane flow of anions down their electrochemical gradient.[10] "Single CFTR channels open and close stochastically in an ATP-dependent manner, the open state catalyzing exclusively "downhill" Cl movement at rates of millions of ions per second, orders of magnitude too high for any enzymatic pump cycle to support."[11] 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[12] ions (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. This results in the movement of water out of the cell by osmosis, and therefore a more fluid mucus.

In sweat glands, CFTR defects result in reduced transport of sodium chloride and sodium thiocyanate[13] 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.[14]


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

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. As a result of these mutations, the movement of water and salt into and out of cells is disrupted. This disturbance leads to the production of a large amount of thick mucus that blocks the developing vas deferens (a tube that carries sperm from the testes) and causes it to degenerate, resulting in infertility.[28]
  • Cystic fibrosis: More than 1,700 mutations in the CFTR gene have been found but the majority of these have not been associated with cystic fibrosis[citation needed]. 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, thin mucus can be removed by cilia. However, thick mucus cannot be removed by cilia, so it traps bacteria that give rise to chronic infections.


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