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Cystic fibrosis is a genetic autosomal recessive disease which means both the parents of the affected would have to be heterozygous carriers for the mutation (Hartwell et al, 2008, pg: 33). In Caucasians, the frequency is 1/2000 (Hartwell et al, 2008 pg: 31). There are several mutations that can cause cystic fibrosis, but the Î”F508 is the most prevalent one (Sullivan et al, 2009). The mutation Î”F508 causes the deletion of a phenylalanine residue on the CFTR (cystic fibrosis transmembrane conductance regulator) protein and alters the 3D structure of the protein resulting in a dysfunctional chloride channel which lacks the ability to control osmotic pressure in the cell. The CFTR is one of the few proteins from the group of AMP binding complex proteins that act as a channel (G. Wieczorek et al, 2008). The mutation of the CFTR gene has several consequences for the resulting protein. The Î”F508 deletes a phenylalanine residue in the protein which alters the active site of the protein. This mutation further causes the protein to be more flexible and allows CFTR to translate back and forth between ABC (AMP- binding complex)-Î± and Î² domains. This flexibility ultimately results in CFTR being incapable of binding to its substrate (G. Wieczorek et al, 2008). Inside the cell the normal CFTR protein is synthesized in the ER and immediately sent to the plasma membrane via vesicles (Ward et al, 1995). But, the mutated protein is not sent to the plasma membrane because the cell has checkpoints to assure that the protein has its native 3-D conformation. If the CFTR fails to have the correct 3-D conformation, the protein is tagged, by an enzyme called GT, and the cell attempts to fix the 3-D shape of the protein (Karp, 2007). Owing that after several attempts the cell fails to fix the protein, the CFTR is destroyed by the ubiquitin-proteosome pathway. This pathway tags the defective proteins with ubiquitin and removes it via proteosome (Ward et al, 1995). Therefore, the mutation not only causes a misshapen protein but it also causes a shortage in the number of chloride channels present in the cell because most of the channels made are destroyed before they can reach the cell membrane.
Some of the symptoms of CF are thickened mucus in the lungs particularly which obstructs the airway and causes breathing problems. This occurs due to the lack of ionic equilibrium on both sides of the organ epithelium. The thickened mucus encourages bacterial infection in the organs by increasing the pressure on the epithelial layer, damaging lubrication in the lungs and creating an ideal environment for the bacteria to thrive (Worlitzsch et al, 2002). There are a range of pathogens that can build up in the mucus layers like P. aeruginosa and S. Aureus. CF is also characterized by thickened mucus in other organs like the intestine, pancreas etc causing malfunction of the digestive system as well(Saeed et al, 2007). As a result of the pathogenic infection, the immune system responds by releasing cytokines and chemokines into the organs which ultimately cause inflammation and chronic lung diseases found in CF patients (Goss et al, 2006).
CF patients can be treated for symptoms and infection with antibiotics such as Tobramycin can be used for treating P. aeruginosa or azithromycin to treat other kinds of bacterial infection or the patients can be treated for anti-inflammatory responses (Saeed et al, 2007). Although, these antibiotics and other interventions get rid of the symptoms they do not restore the function of the mutated chloride channel and there is still an ongoing ionic gradient difference on either side of the epithelium. If there was a way to allow the misshapen protein to reach the plasma membrane by stopping the ubiquitin-proteosome pathway, then the CFTR channel proteins could reach the cell membrane and work. Novel treatments like miglustat have shown to atone for the effect of CFTR Î”F508 deletion in a gradual, reversible manner (Norez et al, 2009). Miglustat does not really correct the mutation but it takes a different route to accomplish the function of the chloride channel. Miglustat works by reducing the absorption of sodium ions across the membrane through ENaC sodium channels and maintaining the ionic gradient across the cell. This maintenance of the ionic equilibrium directly avoids mucus build up and explains the "correction" of the mutation (Noel et al, 2008). Miglustat also avoids the protein from being destroyed by the ubiquitin-proteosome pathway by inhibiting the GT enzyme from tagging the misfolded protein resulting in less CFTR proteins being degraded and more proteins reaching the plasma membrane (Norez et al, 2009). Another seemingly effective therapy for CF is lung transplant. Although lung transplant is the best available therapy out there, it does not cure mucus build-up and problems that arise in other organs like the pancreas and liver etc. A study showed that the mean years of survival after lung transplantation was about 6.4 years in adults (Adler et al, 2009).
Cystic fibrosis, which once meant a high mortality rate and painfully short life, has become manageable with all the advances in medicine. Today patients with CF can live up to 18 years of age or more. Although patients may have to expend a lot of money in treatment and maintaining their body, the life expectancy of CF has improved dramatically since the discovery of CF in 1938. As a result of longer life expectancy there are new CF related diseases that are emerging like diabetes; gastrointestinal problems which would affect normal non-CF patients as their age progresses anyway (review Davis, 2006).