Abstract
Cystic fibrosis, a chronic disease that develops gradually is a disease that would cause one to have a reduced life expectancy. This is a disease that affects some systems in the body specifically the digestive, reproductive, and the respiratory affecting young adults as well as children. This may also affect the sweat glands. This is the disease that this paper would look into. What is really cystic fibrosis and what are the causes of the said disease.
The paper will discuss the molecular cause of the disease that affects 1 in every 3,300 Americans and is a common disease among the Caucasians. This is a disease that would cause shortening of one’s life span into 30 years the most (Stafferton, 2007). The research would look deeper into what the disease is, how an individual is prone to having it and the other causes that might contribute to the disease. This information would help us better understand what the disease is all about.
Introduction
Cystic Fibrosis (CF) is a disease that can be inherited. This is a disease that affects the ion transport of the epithelial cell that in turn affects the systems in the body. This can also cause a progressive disease of the lungs and insufficiency in the pancreas’ exocrine function during the childhood stage. Little is known about the disease until this was given attention to. In 1989, the gene that is responsible for the said disease was successfully cloned by Tsui and his colleagues (Shalon and Adelson, 1996).
In the data that was collected by the Cystic Fibrosis Foundation, they found out that the disease affected 20,000 Europeans, 30,000 Americans and 300 Canadians. Although this disease affects all people of any race or ethnic group, this is more common among the whites which have their roots traced back in Northern Europe. This is the disease that affects around 2500 babies in the United States alone every year and there is 1 in every 20 Americans are unaffected carriers of the said disease (Tait, 2001).
Cystic Fibrosis, autosomal recessive disorder, is caused by the mutations inf the CFTR gene (or the cystic fibrosis transmembrane conductance regulator). This is an inherited disease that if a person has one copy of the altered gene, they are asymptomatic but are carriers of the said disorder. This is a disorder that will appear only when two altered genes are present in a person (Tait, 2001).
This is a disorder that affects people in different ways with different manifestations as this disease affects many organs in the body. It may affect the sweat glands, the respiratory system and the digestive system to mention a few. Thus the signs and symptoms of the disease may vary from one person to another.
With this paper we will be looking deeply into the molecular cause of cystic fibrosis to have a better understanding of the disease. This paper will discuss what the disease is, the incidence, and the gene that is involved in the disorder and its normal function. The paper will also discuss how the gene causes cystic fibrosis.
What is Cystic Fibrosis?
Cystic fibrosis is a disease that is a heterogeneous genetic type. This is a genetic disorder that is believed to be caused by the mutation in the cystic fibrosis transmembrane conductance regulator or the CFTR gene. There are two types if the said disease one being the classic cystic fibrosis and the other one being the nonclassic cystic fibrosis. The classic CF is the one that does not contain any CFTR functional protein. This is the disease is characterized by chronic bacterial infection that occurs in the airways and in the sinuses. This can also cause fat maldigestion because of the insufficiency on the exocrine function of the pancreas.
This also causes infertility because of the obstructive azoospermia. The person may also have increased concentrations of chloride in the sweat. The nonclassic cystic fibrosis on the other hand has one copy of the mutant gene that gives the person a better chance of survival because there are still functional CFTR genes. The person having this type of cystic fibrosis may not have overt signs of the said disease. A part of the pancreatic exocrine function is preserved, the sweat chloride is lower compared to the classic CF (Knowles, Michael and Durie, 2002).
This disorder causes thick mucus production of the body that may lead to conditions such as pneumonia, infertility or even diarrhea and poor growth. This is a fatal disease that can even take a child’s life. This is a disease that shortens a person’s life to 30 years until better treatments are found (lenetix.com, 2007).
Incidence of Cystic Fibrosis
Cystic fibrosis is a disorder common to the white people which is considered to be a fatal autosomal recessive childhood disorder. In the Untied States alone this disorder affects 1 in every 1900-3700 live births (Report of a joint meeting of WHO/ECFTN/ICF(M)A/ECFS, 2002). In Europe this is a disease that is well documented affecting 1 in 2000-3000 live births. In North America 1 in every 3500 is affected by the said disorder (Shalon and Adelson, 1996).
In Cuba and in Mexico, the incidence of cystic fibrosis may range from 1 in every 3900 up to 1 in every 8500 neonates born (Report of a joint meeting of WHO/ECFTN/ICF(M)A/ECFS, 2002). Although the disease affects all races and ethnic groups, this is a disorder that is more common among the whites thus there is a low incidence of the said disorder in the African countries. This disorder may have the incidence of 1 in every 17,000 in the black population that are residing in the United States (Shalon and Adelson, 1996).
This is the disorder however may occur in non white people and should be considered when diagnosing the non white when they are showing signs of the said disease. Careful diagnosis should be done to people showing signs of pancreatic insufficiency or those with chronic lung disease or having both of the manifestations.
What is the CFTR gene?
The CFTR gene or the cystic fibrosis transmembrane conductance regulator, ATP binding cassette is a human gene that gives out instructions for the reproduction of the protein called the cystic fibrosis transmembrane conductance regulator. The function of this protein across the cell membrane is to act as an ion channel. These are the channels that are found in the tissues responsible for the production of mucus, tears, sweat, saliva or even digestive enzymes. Chloride is one of the components that are transmitted through this channel which is a response to certain cellular signals.
This is a movement that would help control water movement in the tissues and would help maintain the fluidity of the secretions such as mucus. Under normal conditions, this is the function that would ensure that the organs like the lungs and the pancreas would function properly. This would help lubricate and protect the linings of the airways and the systems of the body such as the reproductive and the digestive systems including other organs and tissues (Genetics home Reference 2008).
Cystic Fibrosis as a Result of the CFTR Gene Mutation
It has been found that there are more than a thousand mutations were identified in the cystic fibrosis transmembrane conductance regulator genes in people diagnosed with cystic fibrosis. Mostly mutations found are changes in the single protein amino acids in the cystic fibrosis transmembrane conductance regulator protein or it could be a deletion of a small amount of DNA from the said gene. The most common mutation that was discovered is the deletion of one of the amino acids at position 508 in the identified protein, a mutation called delta F508. This would result to abnormal breaks in the channels that in turn causes malfunction in the transport of chloride ions.
The mutations that occur in the cystic fibrosis transmembrane conductance regulator genes would also cause alterations in the production, the structure and the stability of channel that is called the chloride channel that would prevent this channel to function properly and would in turn affect the functioning of the organs like the pancreas, lungs, and some tissues. With the presence of the abnormal mucus that would obstruct the airways and the glands then leads to the signs and symptoms of Cystic fibrosis (Genetics home Reference 2008).
Molecular Causes of Cystic Fibrosis
A single locus on the 7th chromosome of humans constitutes the cystic fibrosis gene. It has an mRNA encoded around 6kb long and is 168 kD in weight, is responsible for encoding for a membrane-associated glycoprotein. The cystic fibrosis transmembrane conductance regulator proteins has 5 domains which are the two nuclloetide binding folds, this is responsible for binding ATP which are the NBF1 and the NBF2. Another domains are the two hydropjobic trnsmembrane domains (TMD and the TMD2) and the regulatory domain (Baralle, 2009).
In normal circumstances the 27 exons are found in the mature mRNA, however, the mutations that affects the cystic fibrosis process in splicing affects was known associated in the occurrence of the disease. The cystic fibrosis disease has been associated with the production of the CFTR protein that followed after the loss of the exon 9 in the coding of the mRNA that is caused by the aberrant alternative splicing. Thus studies has been done to explain what might cause the splicing process and an element TG(m)T(n) has been identified which is a polymorphic element. Another polymorphic locus that is based on (TG)m repeats localized in the (T)n tract was found to influence the efficiency of the exon 9 and thus causing the disease (Baralle, 2009).
The mutations found in the CFTR genes causes’ cystic fibrosis. This is a mutation that is located at the log arm of the chromosome 7 that is located at the position of 7q31. This is where the cyclic AMP regulated chloride channel protein of the 1480 amino acids is encoded. The most common mutation found is called the AF508 which is a deletion of the 3 nucleotide base-pair. This mutation causes a missing a phenylalanine at position 508 in the sequence of the amino acids. This is a common mutation that has been found in 70% of the North American cystic fibrosis genes that has been studied. Another mutation known as the mutation W1282X occurs with a frequency of 60% (Shalon and Adelson, 1996).
For over years, mutation has been the identified cause of cystic fibrosis and it was thought that the CFTR gene causes the mutant CFTR proteins to be degraded prematurely thus preventing to reach the surface of the epithelial cells found in the lungs where these proteins are needed. In studies, it was shown that that the CFTR protein was really being degraded in the cells of the before reaching the surface that was found in most CF patients.
However in a recent study done by Balch along with his colleagues, the results showed that the degradation is an effect and not the cause of the problem. In the kids with CF according to Balch, the CFTR protein gets stuck in the endoplasmic reticulum of the cell where the synthesis of proteins like the CFTR and other important functions of the cell takes place. The mutation of the AF508 that is found to 90% of CF alleles that causes the appearance of the signs and symptoms. This mutation, according to Balch, is not the primary cause of the premature degradation but this rather causes the CFTR protein to be stuck in the cell’s endoplasmic reticulum. This is because for the said protein to be out of the endoplasmic reticulum of the cell, the CFTR protein must first engage in a protein complex that is called as coat complex II of the COPII.
This is a component that is responsible for the recognition of the synthesis of the CFTR is done and grabbing it to be placed in the transport vehicle then sending it on its way to the surface of the cell. However, the mutation AF508 loses the CFTR’s “exit code”, the one needed for the COPII to recognize it, thus it fails to engage in the COPII and fails to exit the ER. As the CFTR protein stays in the endoplasmic reticulum and with the endoplasmic reticulum conducting a routine housecleaning, the CFTR now is degraded. Thus the cystic fibrosis can be caused by the failure of the CFTR protein to exit the endoplasmic reticulum because of the missing phenylalanine residue caused by the AF508 mutation (Bardi, 2005).
Who gets the Disease?
As cystc fibrosis is an autosomal recessive disorder, this would need two copies of the CFTR gene for the signs and symptoms of the disease to show. If a person ahs one copy of the said CFTR gene, the person would then be a carrier of the disorder and would show no manifestations of the said disease. If two people who are both carriers of the said disease, their offspring would have two copies of the said disease and would then show the phenotype of he said disorder.
However, people who have the disease would have varied manifestations because the disorder is not only caused by the genes that they have but us also influenced by the environmental factors that they are in. The fact that cystic fibrosis has more than 900 mutations known; this may also cause the varied phenotypes of the cystic fibrosis disorder. Some may even show little or no effect at all to the CFTR function alteration. In a case of a CF patient in Netherlands, CF patients who have one copy of the delta F508 deletion paired with one A455E mutation has a milder pulmonary manifestation compared to the patients who have the homozygous delta F508 (Gene Gateway, 2003).
The different mutations found in cystic fibrosis present different phenotype that would make it harder for scientists to determine a certain cure for the said disorder. Thus further tests are done to people who are diagnosed with cystic fibrosis are done to determine the type of mutation that they have.
Conclusion
Cystic fibrosis is a disease that is caused indirectly by the mutation of the CFTR genes. This is a disease that can be acquired by a person from parents who both have the recessive genes. And since this is a disorder that is identified as an autosomal recessive genetic one, this would need two pairs of the said gene for the person to show its signs and symptoms.
This is a disease that affects the multiple organs of the body that causes serious illness shortening the lifespan of an individual that to 30 years and often cause death among children. However, there are 900 different mutations known to cause the said disease, there are also different manifestations that are caused by the said difference. Some may have milder signs and symptoms of the said disease while others cause a serious illness that would need intensive care of the patient.
Whatever the manifestations of the cystic fibrosis, this is caused by alterations in the structure and the function of the CFTR genes. This would cause the manifestations of the disease thus causing the disorder to become fatal. The disease may be caused by a small part of the cell, but it creates a fatal result affecting major systems in the body.
References:
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