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The Cystic Fibrosis Gene

.. tions have been predicted to alter the selectivity of the chloride ion channels.4 Mutations that are in the first NBF are predominant in CFTR. As previously mentioned, 70 percent of the mutations arising in CF cases are deletions of three base pairs in exon #10. These three base pairs give rise to phenylalanine and a mutation at this site is referred to as DF508.5 Such a mutation appears not to interfere with R-Domain phosphorylation and has even been reported to transport chloride ions.6&7 There are five other frequent mutations that occur in the first NBF. The first is a deletion of an isoleucine residue, DF507.

The second is a substitution of glycine or amino acid #551 by aspartic acid/F551D. The third involves stop mutations at arginine #553 and glycine #542. The fourth is substitutions of serine #549 by various other residues. The fifth is a predicted splicing mutation at the start of exon #11.7 Mutations within the R-Domain are extremely rare. The only reason they do occur is because of frameshifts. Frameshifts are mutations occurring due to the starting of the reading frame one or two nucleotides later than in the normal gene translation.4 Mutations in the second membrane spanning domain of the CFTR are also very rare and have only been detected in exon #17b.

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These have no relevance to mutations occurring in the first membrane spanning domain. They apparently do not have a significant impact on the Cystic Fibrosis Transmembrane Conductance Regulator either.4 Mutations in the second nucleotide-binding fold occur frequently in exon #19 and exon #20 by the deletion of a stop signal at amino acid number 1282. Exon #21 is sometimes mutated by the substitution of asparagine #1303 with lysine #N1303K.4 The Bio-Chemical Defect: Studies of the chloride channels on epithelial cells lining the lungs, sweat glands, and pancreas have shown a consensus in that the activation of chloride secretion in response to cAMP (adenosine 3′, 5′-monophosphate) is impaired in cystic fibrosis cases. Another affected, independently regulated chloride channel that has been discovered is activated by calcium-dependent protein kinases. Sodium ions have also been noted to be increasingly absorbed by apical sodium channels.8 Therefore, the lack of regulated chloride ion transport across the apical membranes and apical absorption of sodium ions, impedes the extracellular presence of water. Water will diffuse osmotically into cells and will thus cause the dehydration of the sol (5- mm fluid layer of the cell membrane) and the gel (blanket of mucus) produced by epithelial cells.9 As a result of this diffusion of water, airways become blocked and pancreatic proteins turn inactive.

An Account of the Absorption and Secretion of Cl-, Na+, and Proteins: An inward, electrochemical Na+ gradient is generated by the Na+, K+-ATPase pump located in the basolateral membrane (the cell side facing the organ it is lining). A basolateral co-transporter then uses the Na+ gradient to transport Cl- into the cell against its own gradient. This is done in such a way that when the apical Cl- channels within the membrane spanning domain open, Cl- diffuse passively with their gradient through the cell membrane.4 In pancreatic duct cells, a Na+, H+-ATPase pump is used and a bicarbonate secretion is exchanged for Cl- uptake in the apical membrane. Chloride ions then diffuse passively when the Cl- channels are opened. Such secretions also allow for the exocytosis of proteins in the pancreas which will later be taken into the small intestines for the breaking down of carbohydrates.4 In addition to the pump-driven gradients and secretions, there exists autonomic neurotransmitter secretions from epithelial cells and exocrine glands.

Fluid secretion, including Cl-, is stimulated predominately by cholinergic, a-adrenergic mechanisms, and the b-adrenergic actions.4 Such chemical messengers cannot enter the cell, they can only bind to specific receptors on the cell surface and transmit messages to and through an intracellular messenger such as Ca2+ and cAMP by increasing their concentration. The intracellular message is transmitted across the cell by either diffusion or by a direct cascade. One example of a directed cascade is the following: Possible Treatments For Cystic Fibrosis: One suggested treatment for CF has been to provide the missing chemicals to the epithelial cells. This can be accomplished by the addition of adenosine 3′,5′-monophosphate (cAMP) or the addition of the nucleotide triphosphates ATP or UTP to cultures of nasal and tracheal epithelia. This has been proven to alter the rate of Cl- secretion by removing the 5-mmeter sol layer of fluid in the respiratory tract.9 Moreover, luminal application of the compound amiloride, which inhibits active Na+ absorption by blocking Na+ conductance in the apical membrane, reduced cell secretion and absorption to a steady state value. Another treatment that has been suggested is to squirt solutions of genetically engineered cold viruses in an aerosol form into the nasal passages and into the lungs of people infected with CF. This is done in hopes that the virus will transport corrected copies of the mutated gene into the affected person’s airways so it can replace the mutated nucleotides.10 This form of treatment is known as gene therapy. A different approach taken in an attempt to cure cystic fibrosis involves correcting the disease while the affected “person” is still an embryo. Test tube fertilization (in vitro fertilization) and diagnosis of F508 during embryonic development can be accomplished through a biopsy of a cleavage-stage embryo, and amplification of DNA from single embryonic cells.5 After this treatment, only unaffected embryos would be selected for implantation into the uterus. Affected embryo’s would be discarded.

Conclusion: Chloride conductance channels have dramatic potentials. One channel can conduct from 1×106 to 1×108 ions per second.8 This is particularly impressive when you consider the fact that there are not many channels present on cells to perform the required tasks. As a result of this, a mutation of one channel or even a partial mutation of a channel, that causes a decrease in the percentage of channel openings, can exert a major effect. Even the mildest of cures altering the Cystic Fibrosis Conductance Regulator in CF afflicted people would lead to significant improvements in that individuals health. Since cystic fibrosis is the most common genetic disorder, particularly amongst Caucasians, in today’s society, intense research efforts towards its cure would be invaluable.

When will cystic fibrosis be completely cured? No one can say for sure but, strong steps have already been taken towards reaching this goal.


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