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I am a senior in high school and I am studying cystic fibrosis.
I don't quite get the function of the CFTR gene as this is my first time dealing with this type of heavy scientific info.
I had searched up its function on a website like this: http://omim.org/entry/602421?search=cystic%20fibrosis&highlight=fibrosi%20cystic
By reading the gene functions section, I learned that CFTR regulate the formation of a chloride channel, changes the regulation of other transport pathways (i.e increase sodium ion absorption in sodium ion absortion). At the same time it also regulate the chloride-coupled bicarbonate receptor. And that is about all I got from that section.
I would greatly appreciate if someone can summarize all the functions of the CFTR gene listed in layman terms (i.e grandma language) and also explain to me why decreased chloride channel leads to thicken mucus or increase sodium ion absorption leads to CF Symptoms. In addition I would also appreciate it if someone can tell me does decreased CFTR gene function also lead to other diseases on top of Cystic fibrosis.
CFTR is the gene which encodes the "Cystic fibrosis transmembrane conductance regulator", which is a membrane protein. Its function is to transport chloride and other negatively charged ion like thiocyanate ions from the inside of the cell to the outside (into the extra cellular space). This happens along a gradient, meaning the ions flow from the place of high concentration (inside the cell) to the place of low concentration (outside the cell). Since this would mean that a negative charge would build up on the outside of the cell, positively charged sodium ions follow the chloride ions by passive diffusion. This ions are secreted into the mucus in the extra cellular space.
This leads to a higher concentrations of electrolytes (salts) outside of the cell, which causes water to leave the cell (following the higher concentration of electrolytes), which makes the mucus thinner.
When the CFTR gene is mutated, this function is impaired and ions cannot be transported across the membrane. This causes a higher electrolyte concentration inside the cell and water stays there. This causes the mucus to get thicker (due to less influx of water), which then can block fine channels of the lung. Additionally bacteria can grow in the thicker mucus, which can cause severe problems as pneumonia. The process functions as shown in the figure below (from here), the sodium ions are not shown here:
If you want to read further about cystic fibrosis, I recommend this website.
Regarding the immune system there are different functions affected. First, the reduced (or prevented) secretion if thiocyanate ions lead to a reduction in the production of Hypothiocyanite ions which kill bacteria. Then different cells which are of importance to a proper immune reaction are impaired in their function, as shown in the figure below (from the first reference):
The function of CFTR is impaired in all cell types, not only in epithelial cells in the lung (although these are the most obvious consequences). In the cells of the immune system (T-cells for example) the intracellular ion concentration is disturbed including Ca2+ which plays an important role in the regulation of other genes. Other observations show that the activation of the immune system itself is also affected.
Further informations can be found in the articles I linked below. They require some knowledge of immunology, but when there are question, ask.
- Immune Responses in Cystic Fibrosis
- The innate immune system in cystic fibrosis lung disease
The CFTR gene is coding a protein called CFTR (Cystic fibrosis transmembrane conductance regulator). This protein is an ion channel, which allows passive transport of the Cl- ions through the cell membrane in both directions. This allows the cells to transport water due to the active transport of Na+ ions. The Cl- ions follow the Na+ ions with passive transport to even up the electric charges, while the water will follow the higher osmolarity created by both ions. (Something similar happens with glucose when you put grapes into water. The glucose cannot go through the membrane of grape cells, but the water can. So the higher osmolarity in the grape cells will suck in water and the grapes will crack.)
Without working CFTR the cells cannot transport too many Na+ ions, because their membrane potential changes too much when the Cl- ions cannot even up the charges, and so the cells would possibly die because of this. (Another possible explanation that the energy barrier would be too much for the Na+ transporter to send through another Na+ ion.)
Without sufficient ion transport the water transport is not adequate in many regions of the body. By cystic fibrosis the most important affected organs are the skin, the lungs, the pancreas and the reproductive organs.
- The skin cannot reabsorb Na+, so it will be salty.
- The lungs cannot send water to the mucus, so it will be too sticky, and because of that it prevents the cilias by cleaning out the pathogens from the lungs. The results are infections, probably pneumonia and cysts in the lungs.
- The pancreas is usually not able to do its job as well. The result are poor digestion, and due to that vitamin absorption problems, e.g. vitamin-D deficiency (and because of that osteoporosis). In many cases the pancreas is completely cystic, and it loses the ability to produce insulin, which leads to diabetes.
- The reproductive organs are affected as well, most of the males with cystic fibrosis are infertile, and about every fifth female as well.
As you already know this is a hereditary disease caused by mutations in the CFTR gene. What you probably don't know that only homozygotes are affected. The prevalence of the mutant alleles is around 1/25 in my country (Hungary), so every 25th person is an asymptomatic carrier and by every 625th marriage there is a 25% chance that the child will be homozygote. The prevalence is dependent on the region, e.g. North- and West Europe is more affected than South- and East Europe.
- Figure 1 - cystic fibrosis homozygote prevalence - Epidemiology: Mutational Diversity-Patterns of CFTR Mutations
Because of the region dependent prevalence of the heterozygotes (and homozygotes) there are theories, which claim that probably there is (or was) a negative evolutionary pressure on the CFTR gene, and the heterozygotes have evolutionary advantage, just like by sickle-cell anaemia and malaria. The CFTR is target of many infectious diseases e.g. cholera, typhoid fever, tuberculosis, etc… , so there are many candidates. Afaik there is no decision yet in this topic.