Cystic fibrosis transmembrane conductance regulator

Cystic fibrosis transmembrane conductance regulator (CFTR) is an ABC transporter-class protein and ion channel that transports chloride 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.

Structure
The gene that encodes for CFTR is found on the human chromosome 7, on the long arm at position q31.2. It contains about 170,000 base pairs. The encoded CFTR is a glycoprotein with 1480 amino acids. It contains two transmembrane regions, each with six spans of alpha helices, that are connected to their cytoplasmatic nucleotide binding folds (NBF). These two nucleotide binding folds are linked to a single R-domain that is a unique feature of this type of ABC protein. ATP is bound to the two NBFs. The carboxyl terminal of the protein is anchored to the cytoskeleton by a PDZ domain interaction.

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 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 opposite direction via the ENaC. 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.

In sweat glands, 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 The Relevance of Sweat Testing for the Diagnosis of Cystic Fibrosis in the Genomic Era).

Mutations
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 (508) 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..

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:
 * ΔF508
 * G542X
 * G551D
 * N1303K
 * W1282X