Cystic fibrosis (CF) is an inheritable progressive disease that results in a thick mucus building up in various organs, including the lungs, pancreas, liver, and intestines. It is caused by mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene.
There is currently no cure for CF, but various therapies are available to help manage symptoms and extend the life expectancy of patients. Research is also ongoing to identify and test new medications.
The CFTR gene
The CFTR gene provides the instructions to make the CFTR protein involved in the transport of negatively charged salts, such as chloride and sodium, over the cell membrane of some organs. The difference in salt concentration over the membrane influences the movement of water in and out of the cell. The protein acts like a channel or gate, which can be opened and closed to control the movement of salts through the membrane.
This process is involved in the regulation of the production of a lubricating mucus that is essential for the functioning of some organs, as well as the production of sweat saliva and tears. For example, in the lungs, this mucus is required for the effective movement of oxygen into the blood.
In patients with cystic fibrosis, a mutation in the CFTR gene disrupts the tightly regulated transport of salts and leads to the mucus becoming thick and sticky. This abnormal mucus can build up in different organs, creating problems.
For example, it can cause inflammation and repeated bacterial infections in the lungs, leading to scarring (fibrosis) and respiratory failure. Thick mucus can also prevent the digestive enzymes required to break down food from being released, leading to insufficient nutrients being absorbed.
Types of CF-causing mutations
Over 1,700 different CF-causing mutations have been identified in the CFTR gene to date. A mutation is a change in the DNA, which alters the instructions for the protein that the gene encodes for. Different mutations can cause symptoms of varying severity and may need to be treated in different ways.
CF is a recessive condition, meaning that a child will need to inherit two mutated copies of the CFTR gene, one from the mother and one from the father, to develop CF. A person with only one mutated copy can pass on the altered gene, but will not experience any disease symptoms — they are referred to as “CF carriers”.
- Class I: where the mutation causes no CFTR protein to be produced at all.
- Class II: where the mutation results in a misshapen CFTR protein that cannot move salts across the cell membrane effectively. The most common CF mutation (called F508delta) belongs to this class.
- Class III: where the mutation causes the “gate” that allows the salts to pass through to be permanently closed.
- Class IV: where a mutated CFTR protein folds into the correct shape, but still cannot move salts across the cell membrane effectively.
- Class V: where a mutation causes a reduced amount of functional CFTR to be produced.
- Class VI: where an unstable CFTR protein is produced, resulting in it being broken down more quickly.
Many new approved and investigational CF treatments specific to a particular class of mutation are being developed. For example, Orkambi (lumacaftor/ivacaftor) is designed to treat the common class II mutation, F508delta, by enabling the CFTR protein to fold correctly. Kalydeco (ivacaftor) may be given to patients with some class III mutations.
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