Cystic Fibrosis information

Problem Summary #1: Cystic Fibrosis

As of 2010, 1 child of every 3600 born will have cystic fibrosis (CF) (Canadian Cystic Fibrosis Foundation, 2002). CF is an autosomal recessive disease which causes dysfunction of the secretory glands found in the lungs, pancreas, sinuses, liver and intestines. CF is characterized by the overproduction of abnormally viscous and sticky mucus from these glands which interferes with breathing and digestion. In areas such as the lungs, CF attributable mucosal build up is found to block airways. Because of this, bacterial microorganisms tend to remain in the lungs for longer periods leading to repeated infections (Linsdell, 2005). Enzymatic ducts which exist in the pancreas are also found to be blocked in CF patients. This results in a lack of digestive enzymes present in the intestines to absorb nutritive molecules such as proteins, vitamins and minerals (Canadian Cystic Fibrosis Foundation, 2002). Overall life expectancy is quite low for CF patients as degradative damage to such systems begins from childhood. Most die from respiratory failure due to declining lung function before the age of 40 (Canadian Cystic Fibrosis Foundation, 2002). However, as treatments for CF continue to improve, so does life expectancy for those who have the disease. This paper will look to elucidate the basal cellular and molecular mechanisms attributable to cystic fibrosis and direct attention to the possible therapies which exist based on knowledge gained through such foundational research.

At a molecular level, the causative agents behind cystic fibrosis are genetic mutations to a single gene and its corresponding protein, known as the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). Over 1300 types of errors within the CTFR gene have been identified as causative agents for CF. Each genetic error subsequently results in CFTR proteins malfunctioning in a different way (Linsdell, 2005). The “DF508 /DI507” mutation is the most prevalent CFTR mutation amongst affected Caucasian populations in Canada at 71.2% (Canadian Cystic Fibrosis Foundation, 2002). This particular mutation is a three base pair deletion between positions 507 & 508 of the CFTR gene (Linsdell, 2005). Two A-A pairs and a G pair between 507 and 508 will be deleted (Linsdell, 2005). On the polypeptide, the DF508 /DI507 mutation is a loss of phenylalanine residue (Short et al, 1998). When looking even closer at the molecular mechanisms, it is seen that prior to being integrated with the plasma membrane, “chaperone proteins” are attached to the CFTR protein and aid in the process of protein folding (Bebo et al, 1998). Such is not seen with mutated CFTR proteins as the “chaperone protein” is not removed following attachment and interferes with protein folding (Bebo et al, 1998). The CFTR is subsequently marked in the endoplasmic reticulum for degradation prior to maturation (Bebo et al, 1998). This eventually leads to the formation of abnormally folded CFTR proteins that do not reach or attach to the plasma membrane properly.

At a cellular level, the causative agents behind cystic fibrosis present themselves with much more complexity and raise interesting questions about treatment possibilities. Functionally, the CFTR protein is an integral membrane protein which acts as chloride channel for salt transport across many different epithelial cell types of the body (Short et al, 1998). The CFTR functionality explains why mutations to this protein result in abnormal cellular water retention capabilities. The CFTR protein structure consists of a 1480 amino acid polypeptide chain grouped in relative domains: two homologous repeat domains each containing six transmembrane (TMs) regions followed by two intracellular nucleotide binding domains (NBDs) with both halves joined by an intracellular regulatory (R) domain (Linsdell, 2005). It is this mutation which causes the abnormal gland secretions found in all CF patients. The fluid produced by these glands contains proteins crucial for the relative “digestive, lubricative, or protective functions” (Jahic, 2003). What is critical to note is that the epithelial tissues and its “ionic, protein, and water composition” (Jahic, 2003) directly affect the protein composition of such secretions.

Under normal conditions, the CFTR protein is modified by the endoplasmic reticulum and is reintegrated into the plasma membrane of the epithelial cell. An increased negative potential gradient is formed across epithelial cells as chloride ions enter the lumen from the extracellular space. Next, sodium ions progress across the gradient into the lumen as well, causing a high concentration of ions to form. Osmosis consequently occurs as water enters the lumen from the extracellular space. This inherently causes for less viscous mucus containing mostly water and little NaCl as water flows into the mucus from the cell.

Under the conditions of cystic fibrosis however, the CFTR proteins do not fully integrate themselves into the plasma membrane (Bebo et al, 1998). In CF patients, the “luminal side” of the concentrated gland presents a higher than normal negative ionic potential (Bebo et al, 1998). A decreased permeability to chloride ions in the cell membrane is attributable to this. As indicated by (Jahic, 2003) this is shown by the high concentration of NaCl found in the sweat of affected patients (also the basis for CF diagnostic “sweat test”). A decreased uptake of chloride ions conversely causes for an increased uptake of sodium ions furthering the relative negative ionic potential. The increase in chloride ions and decrease in sodium ions decreases the osmotic movement of water into the airway, thereby increasing the viscosity and salt concentration of the mucus secretions. This type of mucus has been shown to be harder to remove then the normal mucus produced (Short et al, 1998). The resultant highly viscous mucus presents itself as an ideal medium for bacteria, thereby increasing the prevalence of chronic respiratory infections.

Although there is no current cure for CF, many avenues are being explored for new therapies. The most sought after during the early 2000s was the idea of gene therapy by aerosol. The idea was to be able to implement a normal CFTR gene into diseased cells as this would cause the production of functional CFTR proteins in cells. The methods employed were adenoviral vectors cationic liposomes (Rochat et al, 2002). Early trials demonstrated that gene transfer from the inner lumen to the respiratory epithelium could be achieved in vivo, but only with low efficiency (Rochat et al, 2002). On the other hand, a new therapy which has been recently developed looks to minimize the apparent activity of chaperone proteins found within the endoplasmic reticulum (ER) in order to minimize degradation of CFTR proteins (Egan et al, 2002). This new therapy may prevent the accumulation of premature CFTR protein in the ER.

It may be conclusively stated that any future pursuits to rectify the basic defect in CF will only rest upon the need for greater understanding of the basal links between the cellular and molecular mechanisms responsible for causing cystic fibrosis.


Canadian Cystic Fibrosis Foundation. (2002). Report of the Canadian Cystic Fibrosis Patient Data Registry 2002. Report of the Canadian Patient Data Registry. 1 (1), 1-8.

Linsdell, Paul. (2005). Mechanism of chloride permeation in the cystic fibrosis transmembrane conductance regulator chloride channel. Experimental Physiology. 10 (91.1), 123-129.

Short, Douglas. Trotter, Kevin. Reczek, David. (1998). An Apical PDZ Protein Anchors the Cystic Fibrosis Transmembrane Conductance Regulator to the Cytoskeleton. The Journal Of Biological Chemistry. 273 (31), 19797-19801.

Bebo, Zsuzsa. Mazzochi, Christopher. King, Scott. (1998). The Mechanism Underlying Cystic Fibrosis Transmembrane Conductance Regulator Transport from the Endoplasmic Reticulum to the Proteasome Includes Sec61b and a Cytosolic, Deglycosylated Intermediary. The Journal Of Biological Chemistry. 273 (45), 29873-29878.

Jahic, Nerma. (2003). Cystic Fibrosis Transmembrane Conductance Regulator Tutorial . Available: Last accessed 12 February 2010.

Rochat, Thierry. Morris, Micheal. (2002). Gene Therapy for Cystic Fibrosis by Means of Aerosol. Journal of Aerosol Medicine. 15(2), 229-235.

Problem summary # 1

Personal reflection:

Overall, this was an interesting project to take on. This was a new disease that I had often heard about but truly knew nothing about. I find that I had truly learned a lot about this disease from a breathe of angles. I had encountered some difficulty in finding the actual primary sources to use and to develop my paper. I had found a very informative website which explained everything wonderfully, but was confused as to whether I was able to use it as a reference or not. One of the main problems i encountered was time! Despite being given an extra day, i found it hard to to truly give enough time to this essay as i had many other exams and papers to study for despite it being due during reading week. Even as i am writing this, i see that i am 2 minutes over the deadline! Time seems to always been an issue with papers such as these. It seems the actual reference searches are where most students encounter troubles. The development of the paper never takes long, but references do. If I were to change anything for next time, it would be to be more conscise in my writing (word count was tough to adhere to) and to try and somehow find the extra time to work on essays!

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