Causes and Effects of Cystic Fibrosis

Problem Summary #1 - The Causes and Effects of Cystic Fibrosis

Cystic fibrosis (CF) is one of the most common life-shortening inherited diseases among the human population, with the majority of sufferers only living to their late twenties (Row, et al., 2005). Its effects are progressive and are relatively widespread, ranging from sinus infections to infertility. But the most common symptom, breathing difficulty due to mucus build-up in the lungs, is undoubtedly the most severe effect of CF and is the main cause of early death among CF sufferers (Rowe, et al., 2005). While the majority of these symptoms are treatable, insufficient information about the cellular mechanism of CF and the cell structures it affects is known to develop a cure. In this paper, the information that is known about the cellular effects of Cystic fibrosis will be reviewed and some possible future treatments will be discussed.

It is now known that Cystic fibrosis is caused by a mutation on an autosomal recessive gene. This gene, known as the cystic fibrosis transmembrane conductance regulator, or CFTR gene, codes for the CFTR protein whose phenotypic function is to help create sweat and mucus (Bobadilla, et al. 2002). The protein does this by anchoring to the outer membrane of cells in the sweat glands, lungs, pancreas, and other affected organs in order to form channels through which chloride ions can pass transmembrane to the extracellular space. It can also facilitate opposite chloride ion movement, allowing them to pass into the cytoplasm of sweat duct cells from the extracellular sweat. By mediating this ion movement, and in turn, fluid movement, the CFTR channel plays a crucial role in maintaining cellular equilibrium (Kulczycki, et al. 2003). When this channel is inhibited, chloride ions are trapped inside the cells in the airway and outside of the skin, resulting in a build-up of mucous in the lungs (due to the altered osmotic gradient) and high amounts of salt in the sufferers skin (due to the excess chloride ions reacting with sodium ions in the extracellular space) (Bobadilla, et al., 2002).

But why and at what point does this channel malfunction? To better understand, the various parts of the CFTR complex must be recognized. CFTR is made up of five domains: two membrane-spanning domains that form the chloride ion channel, two nucleotide-binding domains that hydrolyze ATP, and a regulatory domain. The most common CF-causing mutation, delta F508, occurs in the DNA sequence that codes for the first nucleotide-binding domain (Kulczycki, et al., 2003). While there are over 1, 400 mutations that can cause CF, the delta F508 mutation will be focussed on simply because it accounts for two-thirds of Cystic fibrosis cases (Rowe, et al., 2005). This mutation results in the loss of an amino acid (phenylalanine) which produces a hindered CFTR protein that is unable to fold properly. Once this disabled protein reaches the endoplasmic reticulum, the quality-control mechanism of this cellular component recognizes that the protein is folded incorrectly and marks it for degradation (Kulczycki, et al., 2005).

This mechanism is one area being researched in order to find treatments (or even a cure) for CF. The essential principle is to inhibit the quality-control mechanism, therefore allowing the CFTR proteins to bind to the plasma membrane of a cell. Since it is known that CFTR is retained in the endoplasmic reticulum by calcium ion-dependant proteins and that these proteins are directly responsible for the inhibition of CFTR channel formation, the theoretical treatment is to deplete the calcium ion stores within the endoplasmic reticulum. This, in turn, would disable the quality-control proteins and allow for the CFTR membrane channels to form (Bobadilla, et al., 2002).

But this treatment is expected to have broad side effects. Considering it works on such a basic cellular level, it is presumed by the research community that it will have quite drastic effects on all calcium ion-dependant proteins. Particularly for this reason, other potential treatments are being explored, including more symptom-directed means (Bobadilla, et al., 2002).

One of the major respiratory problems occurring with CF sufferers is the colonization of bacteria in the altered mucus of their lungs (Saiman, 2004). Due to the thick mucus environment, it is quite difficult for immune cells and antibiotics to have a significant effect on these bacteria. So, rather than directly targeting the bacteria, treatment methods are being investigated based on the current theories as to why these bacteria can thrive so well. One of these theories suggests that the lack of chloride ions exiting through the CFTR channel leads to the accumulation of more viscous, nutrient-rich mucus in the lungs that allows bacteria to hide from the body's immune system. Another leading theory proposes that the CFTR protein failure leads to an increase in sodium and chloride uptake, increasing water reabsorption and creating dehydrated and thick extracellular mucus (Saiman, 2004). Because so little is known about these bacteria colonies, however, viable treatment options that target them are not yet in use.

Until more efficient therapies are discovered, Cystic fibrosis sufferers will have to continuously manage their symptoms in order to reduce organ damage and to live pseudo-normal lives. While many of the cellular aspects of this disease are known, much remains to be found.


Bobadilla JL, Macek M, Fine JP, Farrell PM (2002). Cystic fibrosis: a worldwide analysis of CFTR mutations--correlation with incidence data and application to screening. Human Mutation. 19 (6): 575-606.

Kulczycki LL, Kostuch M, Bellanti JA (2003). A clinical perspective of cystic fibrosis and new genetic findings: relationship of CFTR mutations to genotype-phenotype manifestations. American Journal of Medical Genetics. 116 (3): 262-7.

Rowe SM, Miller S, Sorscher EJ (2005). Cystic fibrosis. New England Journal of Medicine. 352 (19): 1992-2001.

Saiman L (2004). Microbiology of early CF lung disease. Paediatric Respiratory Reviews. 5 Suppl A: S367-9.

Personal Reflection

Overall, it was easier to find information on Cystic Fibrosis than I had initially thought. I was expecting there to be much fewer articles pertaining to the genetic malfunctions causing the CFTR mutation, and had planned on spending a much greater amount of time on finding relevant articles about this topic. Luckily this was not the case! The biggest challenge I faced while doing this problem summary was trying to grasp the concept of how this mutation biomedically alters one's phenotype. Once I was able to understand this, I had a relatively trouble-free time completing this assignment.

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