Cystic Fibrosis and the Cftr Gene
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The proper APA Style reference for this manuscript is:
BASS, D. M. (2000). Cystic Fibrosis and the Cftr Gene. National Undergraduate Research Clearinghouse, 3. Available online at Retrieved April 30, 2017 .

Cystic Fibrosis and the Cftr Gene

Sponsored by: TODD ECKDAHL (
Abstract: Cystic fibrosis is a very serious disease. It is among the leaders in killers of its type. It can causes many problems to the internal organs and affect many areas. It is caused by the cystic fibrosis transmembrane conductance regulatory gene. There has been and continues to be extensive research done on this mutation and what may be done to treat or cure it. They have made much progress in the research of cystic fibrosis, but much is yet to be found. It has a long history and there is still much more to come.

Nature of the Disease: Cystic fibrosis is a disease that has been around for a long time. Reference to cystic fibrosis can even be found in European folklore which says woe to the child which when kissed on the forehead tastes salty. He is bewitched and must die. In this time a child with cystic fibrosis would mostly likely have died because the advances in research in this area had not yet been found. For a long time the cause to cystic fibrosis was unknown, but there were many conditions found to be related to it. The largest of these was the excessive amount of salt in the sweat, which is what European folklore was referring to. Many different organs and systems were found to be affected by the cystic fibrosis disease. Some of these areas include the airways, the liver, the pancreas, the small intestine, and the reproductive tract (Welsh et al. 1995). In the airways there is a clogging and infection of the passage, which cause troubled breathing. This may progress and destroy the lungs. Lung disease is what accounts for the majority of deaths in cystic fibrosis patients. In the liver there can be a plugging of the bile ducts, which impedes digestion and disrupts liver function. A change in the ducts of the pancreas can keep it from delivering important digestive enzymes to the bowel. This can result in diabetes. In newborns an obstruction of the gut may occur because of thick stool, which requires surgery. Lastly, the reproductive tract can be affected in 95% of males by causing them to be infertile due to the absence of the fine ducts. On occasion women may also become infertile. Due to the large number of problems caused by cystic fibrosis and the deaths resulting from it caused a race to find the mutation that may be the cause. This race came to a culmination in 1989, when a large group led by Lap-Chee Tsui and John Riordan announced that it had isolated the gene. They named the gene that the found to be the cause the cystic fibrosis transmembrance conductance regulatory gene or CFTR. They named it this knowing the effect that this gene had on the chloride channel. It was the affect of this gene on the chloride channel that was causing the excessive amount of salt in the sweat. It was also found that the genotype was just a simple recessive trait, but phenotypes could not be linked directly to the specific genotypes due to the fact that two mutant alleles can be received from both parents and other factors. The finding of this gene was a huge step in the diagnosis and treatment of the disease. They now knew what was causing all of these symptoms in the body and research could now be done to try and stop cystic fibrosis. Research to find a cure began almost immediately. There have been many different ideas looked into, such as gene therapy, drainage of the airways, and inserting a pure gene into cells with the mutant CFTR gene. Nothing has been found to cure cystic fibrosis as of yet, but there are things being done to help treat it. There have been procedures developed to drain the airways and passages to allow for easier breathing. It is highly recommended that there be check-ups regularly to check on patients with cystic fibrosis.

Genetic Basis: The pattern of inheritance for the cystic fibrosis disease is an example of an autosomal recessive trait. There is a 1/2500-incidence rate for the disease. It also carries a 1/25-carrier rate for Caucasians of Northern European extraction, which is the most common genetic disease amongst Caucasians. There is also a 1/65-carrier rate in African Americans. As research on CF (cystic fibrosis) continued there came a rush to discover the gene responsible. In 1989 Lap-Chee Tsui and John R. Riordan discovered the cystic fibrosis transmembrane conductance regulatory gene or CFTR. Many procedures have been performed to establish and back up this conclusion. This gene has been isolated and cloned by the procedures of YAC (yeast artificial chromosome), a process of chromosome walking and jumping, and using cell libraries. They took the cell libraries from epithelial cells isolated from airways of CF patients and exposed these cells to cyclic AMP. This normally has no effect on patients without CF. They found that this caused chloride to stream out of the treated cells. There have been a number of studies done on the cystic fibrosis disease in attempt to map the diseased gene to a certain chromosomal location. To do this scientist used genetic markers such as PON, COL1A2, D7515, and CF. These different combinations were used together and probed. They then came up with the conclusion that these items were in the order of COL1A2, D7515, PON, and CF and were all found on the seventh chromosome. They cystic fibrosis disease caused by CFTR (cystic fibrosis transmembrane conductance regulatory) gene was found to be at the location of 7q31.2 (Grandy et al. 1994). By referring to the diagram 1.1 you can see that the CFTR gene is found on chromosome seven. The disease is caused by a specific change in the nucleotide sequence causing a protein to be deleted (Welsh et al.1995). As you can see by the blown up region of the map this change is a deletion of the base pair sequence CTT at the amino acids of 507 and 508. This mutation is referred to as the ^F508 mutation. When these three base pairs are cut it causes the amino acid sequence of to now read isoleucine, which can still be read with the sequence of ATT because of the wobble theory, followed by the amino acid glycine. This means that the amino acid phenylalanine at position 508 is not read causing the mutation. This ^508 mutation has been found in 70% of all patients with cystic fibrosis. An alternate mutations do exist to explain the other 30%, but very little is known about these other than they all deal with the same deletion of the amino acid phenylalanine.

Gene Expression: Expression of the cystic fibrosis transmembrane conductance regulatory gene is found in areas that are lined with epithelial tissue. Some of these places include the gastrointestinal tract, salivary and sweat glands, cervix, uterus, fallopian tubes, epididymis and the vas deferens. These tissues all show some form of pathological involvement with cystic fibrosis. The direct transfer of the CFTR gene showed Gene expression in lung epithelium to the airway. After two days, analysis of a rat, in situ, showed the CFTR gene being expressed. (Rosenfeld et al. 1992) Upon further investigation a northern analysis of lung RNA revealed human CFTR transcripts for up to six weeks. Human CFTR protein was detected in the epithelial cells using anti-human CFTR antibody eleven to fourteen days after infection. Gene expression has also been show to exist in the intrahepatic bile ducts in vivo (Hyde et al. 1993). In some organs CFTR expression occurs at different times in a person`s life. In the lungs expression is found to be the highest in infants, however no lung disease is found to exist during this time. As the infant becomes older, gene expression decreases, but the disease start to show. The reason for this has not yet been found. CFTR expression can be changed during differentiation of intestinal cells and can be modified during transcription and post-transcriptional levels by certain agents. Research is currently underway to try and locate the promoter to find out exactly what happens. The expression of the gene is found in a specific amino acid sequence. This sequence is shown in figure 1.1. By looking at this figure you can see what the normal sequence should be and what happens when a mutation occurs and deletes three of the base pairs, and eliminates the expression of one of the amino acids. It is this mutation that causes the cystic fibrosis transmembrane conductance regulatory gene to be expressed and cystic fibrosis to occur in an individual.

Detection/Treatment/Cures Cystic fibrosis is a disease caused by the cystic fibrosis transmembrane conductance regulatory gene. It can be detected in individuals, but as of yet not cure has been found. One of the main ways to tell or suspect cystic fibrosis is an excessive amount of salt in one`s sweat. This causes them to become dehydrated easier than most. As was the cause during a New York City heat wave. During this heat wave there was a large increase in hospitals in the amount of people with cystic fibrosis. This was due to the excessive amount of salt lost in their sweat (Welsch et al. 1995). The excessive amount of sweat was due to the changes in the chloride channel caused by the CFTR gene. There have also been advances in the ability to test parents to see if they have the disease or may be carriers for cystic fibrosis. It is also now possible to learn if an already developing fetus may carry an altered gene, or if it carries two altered genes, one from each parent. Since the discovery of the CFTR gene there have been many discoveries in the way of treatment for cystic fibrosis. Cystic fibrosis is an ongoing disease that as of yet contains no cure. This is way regular check-ups are necessary. When treating cystic fibrosis one of the main thing that needs to be done is drainage of the airways and passages. This is especially true in the lungs. It allows you to clear the way for easier breathing. The salt content of an individual with cystic fibrosis must also be closely monitored. One way to account for the decrease in the chloride channel, causing the low salt content is to increase the activity of different class of chloride channel. This method is currently being tested. One area that they are looking into is the lumenfacing surface of epithelial cells, where channels controlled by calcium channels are known to exist. There are also many other procedures that are currently being tested. One of these is the idea to deliver purified CFTR proteins to cells that need them. Culture studies have shown that protein molecules can correct chloride flow in mutant cells. Another attempt is to use drugs that would cause the mutant CFTR molecules to be escorted from the endoplasmic reticulum through the golgi into the cell membrane. However, the treatment that is currently being heavily looked at, is the idea of gene therapy. There is currently a great deal of research on this. The idea of this procedure is to deliver a normal copy of the CFTR gene to those cells that need it. This would then direct the normal synthesis of the CFTR protein and reverse the causes of cystic fibrosis. The idea of using viruses to enter cells and carry the DNA with them is one of the best-studied methods. There is a lot of look at adenoviruses as gene carriers, because they can naturally infect the airways with little side effects, like the common cold. Hopefully as researchers continue to race for a cure for the mutant cystic fibrosis gene a suitable method will be found. Cystic fibrosis is a serious disease that causes many deaths. There are a large number of organizations that put a lot of time and money into the research and development of a cure. With luck the hard work of all these people will lead to a successful end and a cure to this disease.


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