Cystic Fibrosis
Cystic Fibrosis, commonly referred to as CF, is the most common genetic disease in people with Northern European ancestry affecting 1 in about 3000 live births. The highest CF prevalence can be found in Ireland with 1 in about 1400 live births. In other countries, however, the prevalence is much smaller. For example, 1 in 4000 to 10000 people in Latin America are born with CF and only 1 in 15000 to 20000 in African Americans. Even less people of Asian descent are affected. The CF prevalence of people of African or middle eastern descent is not known.
CF is an autosomal recessive disorder, which means both parents must carry the mutated gene and pass it on for their child to develop the disease. Furthermore, CF is a monogenic disease, which means only one gene is mutated and responsible for the symptoms observed. Although this may sound pretty straight forward, the fact that the protein encoded by the affected gene is present in multiple organs results in a plethora of symptoms that make it very complicated to fully understand and adequately treat the disease.
Most commonly affected organs in Cystic Fibrosis are the lungs, pancreas, sweat glands and gastrointestinal tract. But other organs, like the reproductive organs and bones can be affected as well. Let’s take a closer look at what those symptoms are and what problems they cause.
Lung:
CF-related deaths are most often due to lung associated symptoms. Those can be small airway obstructions, severe or chronic infections, or progressive respiratory impairment. Patients with CF produce a lot of highly viscous mucus that can’t be as easily cleared from the lungs as the normal mucus. This makes breathing hard and creates an environment that favors the growth of pathogens. That’s why many CF patients suffer from constant lung infections and often take long-term antibiotics. As a last resort, CF patients often undergo double lung transplants.
Pancreas:
Similarly to the lungs, CF results in highly viscous secretions of the pancreas that result in destruction of the gland by the time of birth in 85% of patients. This means those patients suffer from pancreatic insufficiency which leads to malnutrition because important digestional proteins can’t be secreted. Oftentimes, islet cells located in the pancreas are also damaged leading to the development of CF-related diabetes.
Sweat glands:
One characteristic of patients with CF is that they produce extremely salty sweat. There is a spanish folklore from the 17th century that says a cursed child that tastes salty when kissed must soon die. It is believed that this is one of the first direct references to Cystic Fibrosis. Nowadays, sweat tests are a common way to diagnose CF in babies and children. The production of salty sweat is not necessarily life-threatening but it does cause trouble with heat regulation. That’s why one hypothesis regarding the epidemiology of Cystic Fibrosis says that CF prevalence is lower in countries with higher temperatures because heat regulation is more important for survival there than in countries with moderate and low temperatures.
Gastrointestinal tract:
CF patients often struggle with severe constipation, malnutrition due to impaired nutrient absorption and sometimes bowel obstructions that can be very dangerous.
Reproductive system:
Both men and women with CF may suffer from infertility. In men that’s mostly due to missing vas deferens, which are tubes that transport sperm from the testicles to the ejaculatory ducts. In this case men are not sterile and can still have biological children with the help of sperm extraction directly from the testicles. In other cases, however, men have low sperm counts, poor sperm quality or even the absence of any functional sperm, in which case having biological children is more difficult and sometimes impossible. Infertility in women with CF is less common but if it occurs it is due to changes in cervical mucus viscosity which makes natural conception more challenging or it is due to irregular ovulation caused by malnutrition. Those obstacles can often be overcome with the help of assisted reproductive technology.
Bones:
CF patients may also present with osteopenia, which is the loss of bone density and weakening of bones.
How can one gene cause so much trouble?
The affected gene is called CFTR gene. It is located on the long arm of chromosome 7 and codes for the CFTR protein, also called cystic fibrosis transmembrane conductance regulator.
Before we dive into the different kinds of CFTR gene mutations and how they affect CFTR protein function, let’s cover some background to understand what the CFTR protein does in healthy people.
Salt and fluid absorption and secretion are a crucial aspect of maintaining our body’s fluid homeostasis, which means creating an equilibrium or if we want to make it very simple: making sure that all fluids in our body are the way they should be.
CFTR is a protein located in the cell membrane and functions as an anion transporter. In the lung, CFTR channels negatively charged chloride ions from inside the cells into the adjacent airway. CFTR is one of many ion channels that all work together like instruments in a symphony. In a concert, if one instrument doesn’t work, the whole piece sounds wrong. The same is true for ion channels. If one doesn’t work, the whole system gets out of balance and it has detrimental consequences. In the case of CF, a non-functional CFTR protein leads to less anion and water secretion, while cation and water absorption stay unchanged. This explains the thick mucus that CF patients produce in their lungs and have trouble clearing out. Similarly, in pancreas and gastrointestinal tract, the ion and water imbalance is the reason for highly viscous secretions and constipation.
Currently, more than 2000 variants of the CFTR gene are known, although not all of them cause CF. The most common mutation is deltaF508. This means that within the gene three building blocks, called nucleotides, are missing. Those three nucleotides would in healthy people translate into the amino acid Phenylalanine (short F) which is a building block of the CFTR protein. Delta is a symbol that indicates that an amino acid is missing and the number specifies which location within the protein is affected. Therefore, deltaF508 means that Phenylalanine is missing at position 508 in the CFTR protein. The lack if F results in a protein that doesn’t get properly processed on it’s way to the cell membrane and as a result gets destroyed. Cells have mechanisms in place that tightly monitor that proteins are processed and function properly. If they don’t, they have to go. This means that CF patients with deltaF508 mutations end up without functional CFTR proteins. This causes an imbalance in water and anion transport which leads to the symptoms as discussed previously.
The deltaF508 mutation is a class II CFTR mutation. There are a total of six different classes determined by the kind of protein damage. Classes I-III are considered severe cases of CF with most patients suffering from lung symptoms and pancreatic insufficiency. Classes IV-VI are mild CF cases with most patients having less severe lung symptoms and pancreatic sufficiency.
As mentioned earlier, deltaF508 is a class II mutation determined by its transport deficiency. Class I mutations generate intermediate molecules, called mRNA, that are either unstable or truncated and don’t get translated into proteins at all. Therefore, no CFTR protein can be transported to the membrane.
Class III mutations produce proteins that can’t regulate the opening and closing of the channel, leaving it closed and nonfunctional.
Class IV mutations result in proteins that have less efficient anion transport. These proteins still allow some degree of secretion but often at significantly reduced levels.
Class V mutations are a little more complicated. In this case different intermediate mRNA molecules are generated. Some are correct leading to functional CFTR protein. And some are incorrect leading either to nonfunctional proteins or the degradation of the incorrect mRNA. Overall, not enough functional CFTR protein is produced to secure fluid homeostasis.
Finally, class VI mutations produce CFTR proteins that are functional but less stable than the non-mutated versions which means cells degrade them faster.
Research and medicine have come a long way with CF. A few decades ago, babies born with CF didn’t live to experience their first birthday. Today, it is said that the median life expectancy is about 47 years depending on the kind of mutation. Most common causes of death in CF are related to lung problems, such as airway obstructions or severe infections. Life expectancy is also dependent on access to health care which allows patients in more developed western countries to live longer lives with better quality.
Literature used
https://pubmed.ncbi.nlm.nih.gov/27140670/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041544/
