Cystic fibrosis (CF) is a genetic disease caused by a mutation in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) protein gene, with more than 2,000 CFTR mutations identified to date [10, 11]. The CFTR protein is a chloride (Cl-) channel found on the side of the epithelial tissue that faces the external environment (apical membrane), meaning it allows Cl- out of the cell. Water tends to move via osmosis from areas of lower solute concentration to areas of higher solute concentration, with NaCl guiding this movement due to dipole-dipole interactions. Therefore, if Cl- is stuck inside a cell, which can also affect the whereabouts of sodium (Na+), then water is also stuck inside the cell.
At-Home Experiment: Osmosis & Dipole-Dipole Interactions
An often-used experiment in introductory biology courses is the infamous potato slice lab, which can be done at home! In this experiment, potato slices are placed in two separate glasses: one containing plain water and the other salty water [9]. After approximately 30 minutes, noticeable differences in the size and buoyancy of the potato slices can be observed. The slices in the plain water will have expanded and may have sunk to the bottom due to water absorption, while those in the salty water will have shrunk and will be floating because of water loss. This experiment effectively demonstrates the concept of osmosis; the slices in plain water absorbed water because the potato had a higher solute concentration than the water, causing water to move into the slices. Conversely, the slices in salty water lost water due to the higher solute concentration in the water, leading to water moving out of the slices.
There is one place where the CFTR protein works oppositely: sweat glands. CF is often diagnosed using the "Sweat Test", where a doctor will swab the skin of a newborn to test for abnormal amounts of Cl- [11]. This is because, in sweat glands, the CFTR proteins are utilized to allow Cl- into the cell instead of out, with the purpose of being able to reabsorb this important ion after sweating it out. However, if the CFTR protein is not functioning, then Cl- cannot be reabsorbed. People with CF lose 3-4x more NaCl when sweating than the average person [7]. This greatly increases the risk of dehydration in those with CF due to water's tendency to follow NaCl. A sweat test result yielding high Cl- concentration does not necessarily mean someone has CF, but it does suggest further testing to reach a confirmed diagnosis.
CF is an autosomal recessive disorder, meaning it is passed down genetically, and the parents must have at least 1 copy of the CFTR mutation each [2, 11]. When someone has 1 copy of the CFTR mutation, it gets "overshadowed" by the dominant gene, thus it lays inactive. This is known as a CF carrier. If someone has 2 copies of a CFTR mutation, then they would have CF. Furthermore, the 2 copies do not need to be the same mutation; if the person with CF has 2 copies of the same mutation it is known as homozygous, if they have 2 different copies then it is known as heterozygous. This is one of the main reasons why CF can vary so much from person to person.
CF Punnett Squares
When the CFTR gene is mutated, as seen in those with CF, it leads to the CFTR protein not functioning as it should, resulting in certain cell types retaining NaCl and consequently water, effectively dehydrating the external environment of those cells. The cells that normally have CFTR proteins on the apical membrane are epithelial cells of the lungs, upper respiratory tract, pancreas, liver, gallbladder, intestines, sweat glands, and reproductive tract [10]. CFTR mutations can be divided into 5-6 (depending on who you ask) classes based on how the CFTR gene/protein is malfunctioning [6, 15]:
Class I: not made due to synthesis error(s) → CFTR protein never produced
Class II: not processed correctly and discarded by the cell → CFTR protein is produced but does not reach the surface
Class III: does not function correctly and the gate remains shut → CFTR protein is produced, reaches the surface, but doesn't open/function
Class IV: is misshapen so Cl- cannot leave easily → CFTR protein is produced, reaches the surface, but doesn't open/function effectively
Class V: is found in limited amounts on the surface due to variable reasons → CFTR protein may not be produced, may not reach the surface, may not open/function effectively, and/or may not degrade at a normal rate
Class VI: has a reduced half-life → CFTR protein is produced, reaches the surface, opens/functions, but degrades quicker than normal
CFTR Mutations Visualized
Mucus is an important biological liquid that protects us from pathogens such as viruses, smoke, pollen, chemicals, and more, by acting as a physical barrier between ourselves and the environment [13]. Along with that, mucus also humidifies airways and lubricates tissues. It is kept thin and slippery with the help of water, which is what poses a problem with a malfunctioning CFTR protein. When mucus is dehydrated, it becomes thick, sticky, and a perfect environment for microorganisms to thrive [3]. This mucus is the cause of the vast majority of CF symptoms, such as persistent coughing, congestion, and malabsorption.
CF symptoms, like with most illnesses, are not so black and white in their definitions, presentations, and causes. CF affects several bodily systems and can vary significantly from person to person [1, 4, 5, 8, 11, 12, 14]. I would like to note that the following list of symptoms is simplified for educational purposes and is neither a complete list of symptoms nor a reflection of CF as a whole:
Coughing & wheezing → due to excessive thick mucus in airways
Difficulty catching breath → due to excessive thick mucus in airways
Clubbing of fingers & toes → due to less oxygen getting to hands & feet
Nasal congestion → due to excessive thick mucus in nasal cavities
Nasal polyps → unknown cause, but thought to be due to nasal congestion
Reoccurring sinusitis → due to excessive thick mucus in nasal cavities
Pancreatitis → due to excessive thick mucus in pancreatic ducts
Poor absorption of nutrients → due to pancreatitis and excessive thick mucus in the liver & intestines
Diarrhea and/or constipation → due to pancreatitis and excessive thick mucus in the intestines
Poor height & weight growth → due to poor absorption of nutrients
Salty skin → due to inability to reabsorb Cl- after sweating
Fertility problems (especially for those assigned male at birth) → due to anatomical vas deferens, epididymis, and seminal vesicles deformities in those assigned male at birth, unknown cause in those assigned female at birth, but thought to be due to excessive thick cervical mucus & poor absorption of nutrients
Delayed puberty → due to poor absorption of nutrients
References
Centers for Disease Control and Prevention. (2022, November 30). Cystic fibrosis. https://www.cdc.gov/genomics/disease/cystic_fibrosis.htm
The Cystic Fibrosis Center at Stanford. (n.d.). Genetics and CF. Stanford. https://med.stanford.edu/cfcenter/education/english/Genetics.html
Cystic Fibrosis Foundation. (n.d.). Basics of the CFTR protein. https://www.cff.org/research-clinical-trials/basics-cftr-protein#:~:text=When%20the%20protein%20is%20not,symptoms%20associated%20with%20cystic%20fibrosis
Cystic Fibrosis Foundation. (n.d.). Fertility. https://www.cff.org/managing-cf/fertility#:~:text=Women%20with%20CF%20have%20thicker,appropriate%20contraception%20is%20not%20used
Cystic Fibrosis Foundation. (n.d.). The digestive tract. https://www.cff.org/managing-cf/digestive-tract#:~:text=About%2090%20percent%20of%20people,stools%20or%20constipation%20and%20blockages
Cystic Fibrosis Foundation. (n.d.). Types of CFTR mutations. https://www.cff.org/research-clinical-trials/types-cftr-mutations#:~:text=There%20are%20five%20classes%20of,be%20a%20protein%20processing%20mutation
Cystic Fibrosis Western Australia. (2019). Dehydration. https://www.cfwa.org.au/wp-content/uploads/2019/10/Dehydration.pdf
Cystic-Fibrosis.com. (2019, August 2). How does cystic fibrosis cause malnutrition & Malaborption? https://cystic-fibrosis.com/malnutrition
Department of Physics & Astronomy. (n.d.). Permeable membrane - Osmosis instructional resources and lecture demonstrations. The University of Iowa. https://instructional-resources.physics.uiowa.edu/demos/4d5070-permeable-membrane-osmosis
Hanssens, L. S., Duchateau, J., & Casimir, G. J. (2021). CFTR protein: Not just a chloride channel? Cells, 10(11), 2844. https://doi.org/10.3390/cells10112844
Johns Hopkins Medicine. (2021, August 8). Cystic fibrosis. https://www.hopkinsmedicine.org/health/conditions-and-diseases/cystic-fibrosis
Krajewska, J., Zub, K., Słowikowski, A., & Zatoński, T. (2021). Chronic rhinosinusitis in cystic fibrosis: A review of therapeutic options. European Archives of Oto-Rhino-Laryngology, 279(1), 1-24. https://doi.org/10.1007/s00405-021-06875-6
Lillehoj, E. P., & Kim, K. C. (2002). Airway mucus: Its components and function. Archives of Pharmacal Research, 25(6), 770-780. https://doi.org/10.1007/bf02976990
The National Heart, Lung, and Blood Institute. (n.d.). Symptoms. https://www.nhlbi.nih.gov/health/cystic-fibrosis/symptoms
Veit, G., Avramescu, R. G., Chiang, A. N., Houck, S. A., Cai, Z., Peters, K. W., Hong, J. S., Pollard, H. B., Guggino, W. B., Balch, W. E., Skach, W. R., Cutting, G. R., Frizzell, R. A., Sheppard, D. N., Cyr, D. M., Sorscher, E. J., Brodsky, J. L., & Lukacs, G. L. (2016). From CFTR biology toward combinatorial pharmacotherapy: Expanded classification of cystic fibrosis mutations. Molecular Assessed and Endorsed by the MedReport Medical Review Board
All pictures and diagrams used in this article, aside from the cover art, are made by Myr Selvage