If a childs forehead tastes salty, he is bewitched and will soon die. This is a famous belief that people in northern European followed back in the 18th and 19th century. This is an early reference to what is now known as Cystic fibrosis. The first clear and reasonable description of cystic fibrosis came from Dr
Dorothy Andersen in 1938 in her paper "Cystic fibrosis of the pancreas and its relation to celiac
disease: a clinical and pathological study". Before 1938, this disorder was regarded as a celiac syndrome. However, Andersen's studies on 49 autopsies obtained from malnourished children showed that the glandular ducts were plugged by mucus. She also described the characteristic meconium ileus, malnutrition and respiratory complications. She also found microscopic fluid filled sacs (cysts) and scars in the pancrease. This characteristic feature made her to name the disorder as Cystic (fluid filled sace) Fibrosis (scars) of the Pancrease. In addition to the change in pancreatic histology, she also observed squamous metaplasia in the respiratory epithelium, which was very similar to that observed in patients with Vitamin A deficiency. Due to this Andrsen, for many years, supported the major role of Vitamin A deficiency in this disorder. In 1943, Dr Sydney Farber found that this disease was a generalised disease affecting may other organs in addition to the pancrease, and therefore introduced the term mucovisidosis. He also accurately explaind the secondary CF consequences as the respiratory tract damage therefore depends on primary obstruction by thick mucus, failure of proper lubrication of ciliated epithelium and secondary staphylococcal infection" (Farber, 1943). Later in 1953, Paul di Sant'Agnese identified an electrolyte imbalance in (increased salt concentration) in the sweat of CF patients (di Sant'Agnese et al, 1953). He also devised a sweat test, which replaced the previous duodenal juice enzyme content analysis, which due to pancreatic failure was low.
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Andersen and Dr Hodges identified the disease as running in certain families and therefore studies 113 families and discovered a major break through on how the disease is obtained. They found out that the diseases followed a Mendelian homozygous recessive mode of inheritance.
The treatment at that time was mainly a controlled diet and antibiotics to treat infections.
At this time, the life expectancy of new born babies with CF was less than 1 year.
After knowing that the disease was genetic, many research programmes were put in place to identity the cystic fibrosis gene, and in June 1989 the cystic fibrosis gene was discovered on the long arm of chromosome 7, position q31 (Rommens et al., 1989). This discover showed a round of celebration across Europe and USA, the major regions affected with the disease.
The protein synthesised by the CF gene was identified and found to be a transmembrane anion channel, primarily involved in chloride ion transport. Due to its function as a transmembrane transporter, it was named as the cystic fibrosis transmembrane regulator (CFTR).
The discovery of the CFTR gene and its product opened doors to investigations of what actually went wrong in the disease that caused this massive life threatening symptoms. CFTR is the only anionic transporter of the ATP Binding Cassette transporter family.
CFTR is 1480 aminoacid glycoprotein that is mostly found on the apical surface of exocrine tissues where it mediated chloride ion transport. It is the only ATP Biding Cassette (ABC) anionic transporter that is primarily involved in chloride ion transport. The molecular structure of the CFTR is shown in the figure below:
The mRNA of CFTR gene has been found in the epithelia lining of liver, lungs, colon, pancreas, sweat glands, epididymis, vas deference and fallopian tubes (Tizzano et al, 1993). The above picture shows a 2D structure of CFTR. A high resolution, 3-D crystalline array has not yet been determined due to limitations in making homogenous monodisperse quality and quantity samples for large scale crystallization trials. This drawback is one of the major reasons as to why we have a limited precise knowledge on the CFTR channel gating mechanism.
As seen in figure above, the CFTR has 5 domains. 2 of the domains are transmembrane domains that consist of a 6 spanning transmembrane alpha helices. Each of these 2 domains has a nucleotide binding domain, namely NBD1 and NBD2 which bind to a hydrozable nucleotide (pecifically ATP). Thses NBDs are very similar to the NBDs in all other member of the ABC superfamily. This can be shown by the presence of motifs that are diagnostic to ABC family (Manavalan et al,1995). There is one interesting difference in the CFTR NBD1 Walker B residue where a neutral serine instead of negatively charged glutamate or aspartate in all other ABC members. This therefore allows the stable binding of ATP without it being hydrolysed (Aleksandrov et al, 2002). Another characteristic motif present in the CFTR NBDs is the signature motif situated in 3 helices which I thought to rotate when ATP binds (Karpowich et al, 2001). The G551D mutation (second most common in CF) affects this motif and the mutant protein generated is expressed in the plasma membrane but does not open upon PKA phosphorylation.
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These two NBDs are connected by a R domain. This R domain is a unique characterization of the CFTR as no other ABC transporters have it. It also has highly conserved set of phosphorylation sites, which have a primary role in channel gating. Channel gating occurs vi conformational transformation whereby when the R domain is phophorylated by protein kinase A (PKA), the Î±-helical content of the of the domain and the interaction of the R domain with NBD1 are both reduced (Baker et al, 2007). This suggests that he R domain phosphorylation may have a structural impact on other parts of CFTR, which can be studies easily if a 3-D structure was available.
CFTR MECHANISM OF CONTROL
The precise mechanism of CFTR gating and control has not yet been established. There are some many conflicting research outcomes that do not add up to give a precise and universally accepted mechanism of control. The first biochemical evidence of CFTR being an ATPase was given by Canhui Li et al in 1996. The ATP hydrolytic rate (50 nmol/mg/min) is very low, lower than many other ABC trnansporters, some G-proteins such as ras and other ATPases such as the Na+,K+-ATPase. Their results also strongly indicated that ATP hydrolysis and channel activities are greatly coupled. Kinetic analysis also verified that the phosphorylation of the R domain by PKA enhanced the ATPase activity by increasing the affinity of the NBDs to ATP by exposing a second catalytic site on the protein.
The extent of channel gating is quantitatively controlled by the phosphorylation of the R domain by PKA. This phosphorylation however, has a very small effect on the CFTR ATPase activity and is not totally responsible for the binding and hydrolysis of ATP at the NBDs. The two NBDs are both structurally and functionally different. A study by Aleksandrov et al, 2002, suggested that the two domains act independently to each other during ATP binding. None of them have an effect of ATP binding on each other. ATP binding at NBD1 does not necessarily require any cofactors such as a divalent ion like MgÂÂÂÂ2+. In addition very minimal hydrolysis of ATP occurs here and the hydrolysis product (ADP) is retained at the binding site. Things are quite different at NBD2 where MgN3ATP binds and is immediately hydrolysed as it binds. The hydrolysis product is also dislodged form the binding site to allow binding of new MgN3ATP molecules. These findings by Aleksandrov et al, 2002 lead to the conclusion that the NBD1 I a site for stable nucleotide interaction and NBD is the site for high and rapid ATP turnover
A noticeable effect of phosphorylation is that it increases the interaction of the two NBDs and cause channel opening (Mense et al, 2006). In the absence of NBD2, after R domain phosphorylation, channel opening is also seen, therefore suggesting that R domain phosphorylation is not entirely responsible for channel gating (47.
It is the leading genetic killing disease in the nation with 30,000 Americans having it currently. It is not particular about gender and strikes males and females equally often. It is also not picky about what race it affects, though studies indicate that there are more white people with the disease than there are other races with it
Cystic fibrosis is a serious genetically inherited disease that is estimated to affect around 30,000 children and adults in the United States alone (CFF, 2005). In this disease, a defective gene causes parts of the body to produce abnormal sticky, thick mucus. This abnormal mucus causes the lungs to become clogged, and can also lead to serious lung infections that can be fatal (2005). In addition to the negative effect on lung function, the thick mucus also causes an obstructive barrier to the pancreas which results in the patient having difficulty with food digestion as well as nutrient absorption. Cystic Fibrosis can cause complications leading to early mortality (the average age of the Cystic Fibrosis patient today is 30). Yet advances in treatment have steadily increased life the life expectancy of people suffering from this disease
All patients diagnosed with cystic fibrosis have a mutation in both the CFTR gene alleles
THE CFTR TRANSPORTER
SYMPTOMS AND COMPLICATIONS
DIAGNOSIS AND MANAGEMENT OF DISEASE
WHAT IS GENE THERAPY
Previous and current clinical trials
- examples of clinical trials and the method used
- success rate and hopes
Ethics of gene therapy
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"Genetic research today, more than anything else, is probably the most aggressive and advanced it has ever been before. It raises ethical and social issues in many circles, and those issues deserve debate and there is a need to ensure ethical practices when words like "cloning" and human genetic engineering are being used (Howie, 2002, p. 139). However, these ongoing discussions of ethics should not prohibit or bring to an end research that is going to ease the pain and suffering of children and young adults, and improve their quality of life and longevity with less pain."