The cystic fibrosis transmembrane conductance regulator (CFTR) is defective in cystic fibrosis (CF). This protein is a channel that sits on the surface of cells and transports chloride and other molecules, such as bicarbonate. The gene that encodes the CFTR protein, which is also called CFTR, is located on chromosome 7. Mutations in this gene lead to CF. Since the discovery of the CFTR gene in 1989, more than 2,500 mutations have been identified.

The location of the CFTR protein, which is found in several organs, determines where the symptoms of CF occur. The organs that are typically involved in CF are the skin, pancreas and lungs.

Sweat Gland

People with CF has very salty sweat. The sweat gland secretes salt and water some of which is typically reabsorbed in the sweat duct. This reabsorption process is markedly abnormal in people with CF. Chloride transport is virtually eliminated because CFTR located on the surface of the cells in the sweat duct is defective. The lack of CFTR function leads to excess chloride in the sweat of people with CF. The high chloride concentration in the sweat can be used to diagnose people with CF.

Lung

The airways are covered with a thin, layer of liquid called airway surface liquid (ASL) and a mucus gel layer. The mucus layer traps bacteria and foreign particles, while cilia on the surface of airway cells constantly move the particles out of the lungs and toward the mouth. This process, called mucociliary clearance is an important defense mechanism that protects the lungs from infection. The ASL also contains antiproteases, antioxidants, antibodies and other substances that work together to neutralize or destroy invading organisms without damaging the lungs. In CF airways, decreased chloride transport is coupled with excess sodium reabsorption out of the ASL. Since water follows the flow of sodium the ASL and the mucus gel layer become dehydrated.

Pancreas

The exocrine pancreas produces enzymes that digest food. Most people with CF do not make pancreatic enzymes leading to a problem called pancreatic insufficiency. The pancreatic duct cells also secrete bicarbonate into the intestine to neutralize stomach acid via the CFTR channel. The inability to neutralize stomach acid contributes to malabsorption in many people with CF.

More than 2500 different mutations in the CFTR gene have been described. Most of these mutations either substitute one base – the building material of DNA – for another, or delete a small number of DNA bases. The most common CFTR mutation, present in approximately 70 percent of people with CF, is F508del. This mutation is caused by the deletion of three base pairs of the CFTR gene leading to the loss of an amino acid called phenylalanine, abbreviated F, in the CFTR protein.

Everyone receives one copy of the CFTR gene from each parent. To have CF, a mutation must be present on both copies of the CFTR gene, but the mutations do not have to be the same. If a person received one normal gene and one mutated gene, he or she will not have CF, but will be a CFTR mutation “carrier”. One in 31 Americans has one CFTR gene mutation.

Mutations in the CFTR gene can lead to different changes in the CFTR protein. These changes are grouped into 6 classes. People with CF who have some residual CFTR function (Classes 4, 5 & 6) tend to have milder or later onset of symptoms.

When CFTR is defective other channels, including the outwardly rectifying chloride channel (ORCC), the epithelial sodium channel (ENaC), a potassium channel known as ROMK1 and a chloride/bicarbonate exchanger, do not work properly. In addition, other chloride channels present on the surface of epithelial cells may be affected in the CF airways. These “alternative” chloride channels have been proposed as a therapeutic target to enhance chloride transport.

The ORCC is found on the surface of many epithelial cells. Normal CFTR facilitates the transport of adenosine triphosphate (ATP), an energy-carrying molecule, to the outside of the cell, activating ORCC. It is unknown whether CFTR itself or an associated channel actually transports the ATP. However, the mutant CFTR is not able to perform the function of transporting ATP.

The ENaC, a sodium channel found on the surface of epithelial cells, is made up of four subunits: two alpha, one beta and one gamma. Each subunit consists of two transmembrane helices. CFTR also influences the function of ENaC in the lung by decreasing its activity, however, the mechanism by which this occurs is unclear.

As suggested by its name, the chloride/bicarbonate exchanger transports one bicarbonate molecule out the cell for every chloride that it transports into the cell. The chloride is derived from the efflux of chloride through CFTR. Therefore, if CFTR is not functional the activity of this channel will be greatly reduced.

Several other chloride channels are present on the cell surface. The one that may be most influenced by CFTR is the CaCC or calcium-activated chloride channel. The exact protein that creates this channel has yet to be defined. However, it is known that the channel is modulated by the P2Y2 receptor which is activated by ATP. Therefore, the activity of this channel could be influenced by decreased ATP associated with mutant CFTR..