Cystic Fibrosis (CF) is the most common lethal inherited disease among whites, affecting approximately 70,000 people worldwide.1 It is an autosomal recessive disease, and the defective gene involved is the cystic fibrosis transmembrane conductance regulator (CFTR) gene that codes for the CFTR protein. This is an epithelial ion channel that has a role in regulating the absorption and secretion of chloride ions across cell membranes in the lungs, pancreas and other tissues. This allows for the correct balance between sodium and chloride ions.
Although this is a multi-organ disease, 90% of CF cases involve the lungs and it is the progressive lung disease associated with it that is the leading cause of death.1 In the airways, a normal functioning CFTR protein helps keep the mucus layer thin and moist, allowing the cilia to sweep out harmful debris. If that protein doesn't work correctly, that movement is blocked and abnormally thick sticky mucus is produced on the outside of the cell. This mucus clogs the airways in the lungs, and increases the risk of infection by bacteria. In the pancreas, mucus builds up in the ducts, preventing the pancreatic digestive enzymes from getting into the gastrointestinal system. Without these enzymes, the intestines cannot properly digest food. People who have CF often do not get the nutrition they need and have to take oral supplements in order to digest food and absorb nutrients.
More than 1,000 different mutations in the CFTR gene have been identified in cystic fibrosis patients. Different CFTR mutations result in different disease phenotypes.2 Some may have little or no effect on CFTR function, and some may result in milder forms of disease. The most common mutation, DF508 is observed in 70% of the CF population.3 In this mutation, there is a three base pair deletion in the DNA sequence as illustrated in Figure 1. This causes the absence of a single amino acid (PHE) in the final protein product. As a result, the defective protein DF508-CFTR never reaches its final destination at the cell membrane seen in Figure 2. This figure also depicts another mutation seen in approximately 4% of the CF population. In the G551D mutation, the CFTR protein is able to reach the epithelial surface. However its ability to transport chloride ions is very poor. People who are homozygous for the DF508 mutation tend to have the most severe symptoms of cystic fibrosis due to critical loss of chloride ion transport.
A defective CFTR gene can be screened during pregnancy or soon after the baby is born. If the child is homozygous for the mutated CFTR gene, it is important to remember that this does not confirm the worst outcome for the child. The development and progression of CF is highly influenced by environmental factors as well. So the type or severity of symptoms experienced by CF patients cannot be determined alone by the presence of the mutated genes.2 When diagnosing CF, a sweat test is most commonly done and considered the gold standard. It measures the amount of chloride in sweat, and it is present in higher concentrations in CF patients. 4
Although there is no cure for cystic fibrosis, current treatments are helping people live longer by targeting the secondary effects caused by the dysfunction of the CFTR protein. Treatment to aid the lungs mainly work by clearing mucus and preventing lung infections. The common treatments include chest physical therapy, inhaled antibiotics, and bronchodilators.3 Researchers have recognized that a potential treatment for CF could be done by increasing the activity of the defective protein channel in G551D patients. In January 2012, a new pharmacogenomic treatment option was introduced to the market as a result. Kalydeco® (ivacaftor) is a potentiator of the CFTR protein in those with the G551D mutation. It facilitates chloride transport by increasing the time that the CFTR protein remains open, augmenting chloride
