Normal CFTR facilitates the transport of adenosine triphosphate (ATP), an energy-carrying molecule, to the outside of the cell, activating ORCC. The ORCC is found on the surface of many epithelial cells. These “alternative” chloride channels have been proposed as a therapeutic target to enhance chloride transport. In addition, other chloride channels present on the surface of epithelial cells may be affected in the CF airways. 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.

People with CF who have some residual CFTR function (Classes 4, 5 & 6) tend to have milder or later onset of symptoms. These changes are grouped into 6 classes. Mutations in the CFTR gene can lead to different changes in the CFTR protein. One in 31 Americans has one CFTR gene mutation. 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”. 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. 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.Įveryone receives one copy of the CFTR gene from each parent. The most common CFTR mutation, present in approximately 70 percent of people with CF, is F508del. Most of these mutations either substitute one base – the building material of DNA – for another, or delete a small number of DNA bases. More than 2500 different mutations in the CFTR gene have been described.

The inability to neutralize stomach acid contributes to malabsorption in many people with CF. The pancreatic duct cells also secrete bicarbonate into the intestine to neutralize stomach acid via the CFTR channel. Most people with CF do not make pancreatic enzymes leading to a problem called pancreatic insufficiency. The exocrine pancreas produces enzymes that digest food. Since water follows the flow of sodium the ASL and the mucus gel layer become dehydrated. In CF airways, decreased chloride transport is coupled with excess sodium reabsorption out of the ASL. The ASL also contains antiproteases, antioxidants, antibodies and other substances that work together to neutralize or destroy invading organisms without damaging the lungs. This process, called mucociliary clearance is an important defense mechanism that protects the lungs from infection. 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. The airways are covered with a thin, layer of liquid called airway surface liquid (ASL) and a mucus gel layer. The high chloride concentration in the sweat can be used to diagnose people with CF. The lack of CFTR function leads to excess chloride in the sweat of people with CF. Chloride transport is virtually eliminated because CFTR located on the surface of the cells in the sweat duct is defective. This reabsorption process is markedly abnormal in people with CF. The sweat gland secretes salt and water some of which is typically reabsorbed in the sweat duct. The organs that are typically involved in CF are the skin, pancreas and lungs. The location of the CFTR protein, which is found in several organs, determines where the symptoms of CF occur.

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