Farrah Ekbatani
fkg4@wildcats.unh.edu
University of New Hampshire - Durham, NH

Abstract


The goal of this research was to better understand the genetic disease, cystic fibrosis. Symptoms and treatments of the disease were researched and different options were analyzed for their efficiency against various symptoms. Current research that aims to develop improved treatment options were also included to understand where scientists stand at this point with treating the disease. At the cellular level, the chloride ion channel and its mechanism associated with causing cystic fibrosis were discussed in relation to the variation in the cystic fibrosis transmembrane conductance (CFTR) gene. The background genetics and genomics of the CFTR gene were analyzed and reported in order to better understand the many mutations present in the gene and how each one has its own effect. Further comparative genomic analysis was conducted to understand the evolutionary variation of this gene and its importance from species to species. The CFTR gene was determined to have a lot of variation resulting in several different phenotypes. Overall, this research provides insight to further understand the many aspects of this complex genetic disease.

Background


Cystic Fibrosis is an autosomal recessive disease that occurs when there is a point mutation present in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR). To date, there have been hundreds of documented mutations of the CFTR gene, (Tayoun, et al., 2013). Most of these mutations are found to change single amino acids in the CFTR protein or delete a small fragment of DNA from the CFTR gene. The most common mutation, deltaF508, is a deletion of the amino acid at position 508 in the CFTR protein. This results with the immediate breakdown of the abnormal channel, meaning it will never reach the cell membrane for chortled ion transport. Other more common mutations are G542X, G551D, N1303K, and W1282X, (Ara├║jo et al., 2005). Figure 1 illustrates the CFTR protein at amino acids 389-678, deltaF508 along with three other mutations, bound to ATP, (Brynes & Hall, 2015).
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The CFTR gene provides the instructions for the making of the ABC transporter-class chloride ion channel, which is responsible for transporting negatively charged chloride ions into and out of all cells. The channel's main function is to allow chloride ions to flow through the channel to help control the movement of water in tissues. This water movement is essential for the production of thin, freely flowing mucus. A normal functioning chloride channel would result with the movement of chloride ions out of the cell along with water molecules. This channel has four serine amino acids contained in it, which get phosphorylated by the cyclic adenosine monophosphate (cAMP) dependent protein, kinase. This mechanism is dependent on whether or not a peptide hormone is detected by a receptor at the membrane of a cell. The pumping of this channel will not occur unless it is phosphorylated at all four of its serine sites.






Figure 1. Human CFTR aa389-678 (NBD1),
deltaF508 with three solubilizing mutations, bound
ATP (Image retrieved from RCSB The Protein Databank,
http://www.rcsb.org/pdb/home/home.do).

A mutation in the CFTR gene would cause dysfunction in the chloride ion channel function, thus not allowing any flow of chloride ions or water across the cell membrane. This would result in an abnormality of epithelial fluid transport in the cells that line that passageways of lungs, pancreas, as well as various other organs. The abnormal mucus that is produced is very vicious and sticky, which results in clogging of airways as well as various ducts in the body. This
cf-channel.jpgexcess of mucus build-up tends to lead to permanent damage of the respiratory and chronic digestive system.
In Figure 2, both the normal activity and the mutated activity of the CFTR channel is shown. Severity of symptoms resulting from cystic fibrosis varies greatly between patients. Environmental and genetic factors may play a role in the severity of symptoms between patients. For example, patients may have other mutations in genes other than CFTR that might aid in the severity of symptoms a patient experiences, such mutation are still unknown.

Patients with CF tend to easily contract bacterial lung infections and abnormalities, predominantly chronic bacterial airway infection, prominent neutrophilic inflammation and mucus in airways, and bronchiectasis.
These are some of the complications that pair with patients with advanced CF, which can
result in morbidity and death. Currently, there is no cure for CF but there are treatments that work to extend the lifespan of its patients, (Stoltz, et al., 2015). There is a lot of ongoing research that works to find better treatment options as well as potential cures.
Figure 2. Demonstration of both normal and defective
CFTR Channel activity. (Permission for use of this photo granted from the
Genetic Science Learning Center http://learn.genetics.utah.edu).

Next: Current Research

Symptoms and Treatments
CFTR Gene
Comparative Genomics
Results
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