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Cystic fibrosis, or CF, is an autosomal recessive genetic disorder characterized by a thick mucus layer surrounding epithelial cells (Davies, Alton & Bush, 2007). It is the result of a mutation in a gene which codes for a protein called the cystic fibrosis transmembrane conductance regulator, or CFTR (Davies et al., 2007). This essay will outline the function of the CFTR gene and what goes wrong in individuals with cystic fibrosis, as well as treatment options.
In healthy individuals, CFTR is folded in the endoplasmic reticulum with the help of the chaperone protein calnexin (Pind, Riordand & Williams, 1994). Calnexin recognizes and binds to CFTR after glucosidase removes two glucose molecules from the original amino acid chain (Pind et al., 1994). Once the protein has been properly folded, calnexin dissociates from it and it is transported through the Golgi apparatus and sent to the plasma membrane where it can carry out its vital functions (Pind et al, 1994).
The main function of mature CFTR is as an ion transport channel in the membrane of epithelial cells (Davies et al., 2007). It is responsible for moving chloride ions across the membrane into the mucus layer surrounding these cells which are present in the lungs, liver, pancreas, digestive tract, reproductive tract and skin (Davies et al, 2007). When it does this it creates a concentration gradient which draws water into the mucus, making it less viscous and better able to flow. This flow helps the body to get rid of bacteria and reduces infections (Davies et al., 2007).
However, in individuals diagnosed with cystic fibrosis, there is a mutation present on the gene responsible for encoding CFTR. Although there are numerous CF causing mutations, the most common is one, affecting about 70% of patients, is entitled âË†â€ F508 (Davies et al., 2007). This mutation is a three nucleotide deletion which results in the loss of the amino acid phenylalanine in the proteinââ‚¬â„¢s primary structure (Davies et al., 2007). Without this phenylalanine, the protein does not fold properly. As a result the chaperone protein calnexin never dissociates from the protein and, therefore, prevents the protein from leaving the endoplasmic reticulum (Pind et al., 1994). This ultimately leads to degradation of the protein instead of its transportation and integration into the plasma membrane, even though there is experimental evidence showing that this mutated protein is actually quite functional (Pind et al., 1994).
The resulting absence of chloride channels in the plasma membrane of epithelial cells results in a build-up of chloride ions within these cells. This creates a concentration gradient that draws water into the cells and away from the mucus layer. As water moves out of this mucus it becomes very thick and difficult to expel (Davies et al., 2007). This can be very dangerous, particularly in the lungs, because it allows for bacterial colonization and infection causing inflammation, which ultimately results in difficulty breathing and permanent damage to lung tissue (Davies et al., 2007).
Although there is currently not cure for cystic fibrosis there are many promising treatments and therapies, such as the drug miglustat. Miglustat is a ÎÂ±-1,2-glucosidase inhibitor which prevents the removal of two glucoses from the CFTR protein (Norez et al., 2006). This means that, because no glucose is removed, the misfolded CFTR protein does not form an interaction with calnexin and is, therefore, not stuck associated to it. It is instead able to leave the ER and thereby become incorporated into the plasma membrane of epithelial cells. The mutated, yet still functional, chloride channels can then carry out their proper function.
A second effective treatment is a lung transplant. It is usually used as a last resort for those nearing the end of their lives (Rosenblatt, 2009). This is because, not only are donor organs difficult to obtain, but there are also many serious risks involved. Lung transplantation also does not replace all of the tissue affected by CF and a recipient must take medication for the rest of their lives in order to avoid rejection of the organ (Rosenblatt, 2009). However, transplantation is useful in extending life, with over 50% of patients surviving after five years (Rosenblatt, 2009). It has also been shown to improve quality of life for the patient (Rosenblatt, 2009). This is because, as a transplanted lung contains genetic information from a healthy donor, it contains functional chloride channels and is thus CF free.
There are also currently drug therapies being used which are aimed at reducing the affects of CF on the respiratory system. Often these drugs are inhaled and aim to help clear the thick mucus build-up. One such drug currently being used to do this is known as Mannitol, which is delivered via inhalation (Jacques et al, 2008). Mannitol improves symptoms by creating a concentration gradient which draws water out of affected cells (Jacques et al., 2008). This increases the water content of the mucus layer allowing it to be cleared more easily, resulting in a reduction of infection (Jacques et al., 2008).
The mutation of the CFTR gene resulting in degradation of the protein instead of integrations into the plasma membrane of epithelial cells has serious and crippling affects. However, current treatments aimed at preventing degradation of the mutated protein, replacing affected tissue and decreasing mucus viscosity have already succeeded in providing some relief. Constant research is still being done in the hopes of continuing to improve quality of life for sufferers and in order to find a cure.