Cystic fibrosis (CF) is an autosomal recessive genetic disorder (passed down through families) that affects the lungs, pancreas, liver and intestine. It involves abnormal transport of chloride and sodium across the cell membrane, which causes a thick mucus to build up. CF is one of the most common lung diseases in children, and is a life-threatening disorder that causes lung infections and digestion problems. It may also affect sweat glands and the male reproductive system.
Cystic fibrosis refers to scarring (fibrosis) and cyst formation within the pancreas. Symptoms include difficulty breathing, sinus infections, poor growth and infertility. CF is caused by mutations for the protein cystic fibrosis transmembrane conductance regulator (CFTR). This protein channel regulates sweat, digestive fluids, and mucus. CFTR controls the movement of chloride and sodium ions in cell membranes such as the epithelium of the alveoli (air sacs) in the lungs. Generally, individuals without CF have two copies of the CFTR gene. Both of these copies have to be missing or contain mutations to develop CF (recessive).
According to the National Heart, Lung, and Blood Institute (NHLBI), millions of individuals in the U.S. carry the defective CF gene, yet do not present with symptoms. The reason for this is that an individual with CF must inherit two defective genes (one gene from each parent). It has been estimated that 1 in 29 caucasians in the U.S. have the CF gene. In the U.S., most children are diagnosed by the time they are 2 years old. Some CF individuals are left undiagnosed until they are 18 or older because they have a milder form of the disease.
The CFTR protein functions as a channel across cell membranes that generates mucus, sweat, saliva, tears as well as digestive enzymes. This channel has the ability to transport negative chloride ions in and out of certain cells. Chloride transport controls the movement of water in and out of cells (remember that water follows salt). This is important for the production of a free flowing mucus, which lubricates and protects airways, the digestive tract, reproductive tract, as well as other tissues. CFTR regulates sodium channels as well.
Mutations in the CFTR gene located on chromosome 7 alters the chloride channel function preventing the normal flow of chloride ions and water in and out of cells. The tissue produces an abnormally thick mucus that builds up. This is true for the lungs, pancreas, liver and intestinal tract.
To date, over 1,000 mutations have been reported in the CFTR gene. Most of these mutations change a single amino acid in the CFTR protein or delete some DNA. The most common mutation is known as delta F508, which involves a deletion of one amino acid position at the 508 position in the protein. This abnormal protein breaks down after it is made so it never gets to the cell membrane. Depending on the mutations, this changes the production, structure or stability of the chloride channel. Cells carrying the mutations that line the passageways of the lungs, pancreas and other tissues produce an abnormal thick mucus which blocks airways and other glands.
Forms of Cystic Fibrosis
There are many different forms of CF, however there are two of note which includes the Delta F508 mutation and the R117H mutation. Delta F508 is the most common mutation, and is responsible for around 70 percent of all CF cases. The R117H mutation is affected by intragenic changes. This mutation does not generate CF by itself. It requires another CF-causing mutation to occur then R117H can cause disease. Intragenic changes involve the poly-T tract and it comes in three forms designated as 5T, 7T, or 9T. Depending on which poly-T form is present with R117H, you get different outcomes. The R117H mutation is considered a mild form, whereas Delta F508 is considered severe.
Click to read about Cystic Fibrosis Symptoms.