Many pathologies mentioned in this blog have relative heritability because they are polygenic and environmental factors have a strong influence, such as allergies or Crohn’s disease.
Cystic fibrosis does not fall into that category.
It is a chronic pathology of genetic cause with an autosomal recessive inheritance. The pathology is caused by a single gene, but it is necessary to have both abnormal copies to suffer from the disease. If a person has one normal gene and one abnormal gene, they are a carrier.
The culprit is the CFTR gene, an acronym for Cystic Fibrosis Transmembrane Conductance Regulator.
The CFTR Gene and the Information It Contains
The CFTR gene carries the information to encode a protein that acts as a sodium channel. It attaches to the cell membrane and allows sodium ions to pass to the outside of the cell.
In this simple way, it helps control the viscosity of the body’s secretions. Therefore, one of the classic tests to detect the disease is measuring the salt in the sweat of the affected person.
This protein is more important than it seems at first glance.
To begin with, it is found in all exocrine glands (which include the pancreas and liver, among others), intestines, and airways.
As a channel for sodium exit, it works in coordination with other ion channels. Sodium reabsorption is necessary to maintain a positive electrochemical gradient.
It is also suspected to be involved in the concentration of cholesterol and other lipids in the cell in general and in its membrane in particular.
When cystic fibrosis occurs, the main organ affected is the lungs, followed by the intestines, pancreas, and liver. In all of them, it causes the accumulation of thick, sticky mucus that disrupts the normal functioning of the organs.
In 2020, the average life expectancy of patients was around 50 years and increasing.
Among chronic lung pathologies, it is one of the most frequent. In Europe, the incidence is 1 in every 2500/5000 people, making it the region of the world with the highest frequency.
The number of carriers, on the other hand, is much higher. It is believed that, in the United States, 1 in 30 people is a carrier of a variant of the disease.
The Inheritance Left by the CFTR Gene
Heritability is simple, an example of Mendelian inheritance:
- Both parents sick, children sick. What result did you expect?
- One sick parent and one carrier, 50% sick children and 50% carrier children.
- One sick parent and one healthy parent, 100% carrier children (there will always be one abnormal gene and one healthy gene).
- Both parents carriers, 25% healthy children, 50% carrier children, 25% sick children.
- Both parents healthy, healthy children. This option was easy to guess.
Being a carrier is not all fun and games either. Previous studies have theorized that people who carry abnormal gene variants have a higher predisposition to diseases such as bronchitis and lung cancer, although in practice the organ functions normally.
However, the disease is not the same for everyone. Although two people may have the pathology, they do not necessarily show it. This is what we call penetrance, a classic in monogenic diseases.
Penetrance is the proportion of individuals who carry a particular genetic variant and express the corresponding phenotype, the characteristics associated with that variant. A disease caused by a mutation with 80% penetrance means that 80% of people with the responsible variants will have the disease, and 20% will not.
In our case, penetrance is the number of individuals with cystic fibrosis out of the total number of individuals with pathogenic alleles for the CFTR gene.
In the case of cystic fibrosis, its penetrance depends on the mutation responsible for the abnormal activation of the CFTR gene. Most of the more severe mutations also have complete (100%) penetrance. However, in general, penetrance varies greatly depending on the genetic variant in each patient.
Wait, attractive writer, what do you mean by more severe mutations? Does the severity depend on the mutation?
Here we enter another factor, expressivity. The same disease can present different symptoms and effects in patients. This is called variable expressivity, but in both cases, the two people are affected. The intensity and severity of the disease change.
Environmental factors must be taken into account for severity. A person who is obese or a smoker will worsen the symptoms they have due to their genetics.
The variability of cystic fibrosis is enormous because it is a multi-organ pathology. In addition, there are more than 2000 registered variants for the CFTR gene, many of which can cause the disease.
They are all cystic fibrosis, but some more than others.
Recent studies have begun to consider this variability, and the main organs affected in each patient, to carry out personalized treatments.
According to the effects of the mutation, cystic fibrosis is divided into different categories:
- Mutations that affect synthesis. They interfere with the production of the protein, from not producing the protein at all to its incomplete release. Patients completely lack the chloride channel, and expressivity in this category is very severe.
- Mutations that affect protein processing. The protein is synthesized, but there are anomalies in the subsequent steps, such as folding. The protein cannot function, and the cell degrades it, recognizing it as defective. The most common mutation, ΔF508, belongs to this group.
- Mutations that affect the channel. These mutations cause the channel not to open and remain closed. There is protein, but it is not functional.
- Mutations in conductance. Chloride has trouble moving through the channel, but the protein exists, is located in the cell membrane, and performs some of its work (although not very efficiently). Among the bad, it is one of the best options.
- Mutations that cause partial production. There is functional protein, but less than there should be.
Some experts add another additional category, which are mutations that alter the work of the CFTR protein with other channels. A lack of coordination in ion channels.
As you can see, the CFTR gene has taken every opportunity to be complex and has taken advantage of it. That is why the tellmeGen genetic test analyzes many different variants to ensure it functions properly.
