Cystic fibrosis (CF) is a progressive genetic disorder that results in the production of thick, sticky mucus in various organs throughout the body. This mucus can build up and cause respiratory, digestive, and reproductive issues.

CF is caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. More than 1,700 mutations in the CFTR gene have been identified, according to the Cystic Fibrosis Foundation. The mutations are generally grouped into different classes based on how they affect the protein encoded by the CFTR gene and the treatment options available. There have also been several different classification systems proposed over the years, ranging from five to seven different classes of mutations. The classes presented on this page are those proposed in a recent correspondence in the medical journal The Lancet.

CFTR production and function

The information for all proteins in the body is located in the DNA inside cells. DNA is made up of a series of four different nucleotides or “letters” and forms a kind of blueprint for the body. The order of those four nucleotides is important as it contains the instructions about how to make each protein.

To make a specific protein, such as CFTR, an enzyme called RNA polymerase binds to the DNA and makes a copy of the relevant section in a process called transcription. The copy is written in a “language” similar to DNA into a molecule called RNA, which acts like a photocopy of that protein’s building instructions. The copy is called messenger RNA (mRNA) and is then sent out of the cell nucleus before binding with ribosomes.

Ribosomes read the instructions contained in the mRNA and convert the instructions into an amino acid sequence in a process called translation. The amino acid chain then folds up into a specific shape that is relevant to that protein’s function.

Once the CFTR protein has been made, it is shuttled to the outer covering of the cell called the cell membrane. The CFTR protein acts as a channel that allows chloride ions (one of the components of salt) in and out of the cell. When the CFTR protein works properly, it helps maintain the correct level of chloride ions inside and outside the cell. But if the CFTR protein does not work properly or is not present on the cell surface, it causes incorrect chloride levels inside cells, which leads to the formation of thick and sticky mucus.

CFTR mutation classes

Class 1A: no mRNA

The first class of mutations keeps the mRNA from even being synthesized. When a protein is going to be made in a cell, an enzyme called RNA polymerase binds to a region in the DNA called a promoter. The promoter is usually located right before the section of DNA that codes for a specific protein. If the promoter for CFTR contains a mutation, it can lead to the RNA polymerase not being able to bind to the DNA and therefore not copy the message into mRNA. The end result is no CFTR protein being produced at all.

Examples of mutations that lead to no CFTR mRNA include the Dele2,3(21 kb) and 1717-1G→A.

No therapy is currently available to correct this type of mutation. However, there is some research into treatments to inhibit sodium channels or stimulate other chloride protein channels at the cell surface to balance ion levels without the need for the CFTR protein.

Class 1B: no protein

In this class of mutations, the CFTR mRNA is produced but is damaged and cannot be made into protein. There is a specific sequence in the DNA that is then carried over to the RNA, which signals to the ribosome to stop reading the message and marks the end of protein production. Sometimes, because of a mutation, one of these stop sequences appears too early in the mRNA. This results in the production of a shortened version of the CFTR protein, which is then degraded by the cell.

Gly542X and Trp1282X are types of class 1B mutations.

Read-through compounds can help the ribosome skip over the early stop sequence, read the rest of the information on the mRNA, and produce CFTR proteins. Ataluren was one such compound being investigated as a potential treatment for this kind of mutation but its development ended due to failed Phase 3 clinical trial results.

Class 2: no traffic

In this class of mutations, the CFTR protein is made but fails to reach the cell membrane. The CFTR protein has 1,480 amino acids in it and sometimes even a single error can cause the protein to misfold. The cell will often stop misfolded proteins from going to the cell surface and will destroy them.

Examples of class 2 mutations include Phe508del, Asn1303Lys, and Ala561Glu.

To correct the misfolded proteins and help them reach the cell membrane, treatments called CFTR correctors can be used. Some examples of CFTR correctors include lumacaftor/ivacaftor (marketed as Orkambi) and tezacaftor/ivacaftor (marketed as Symdeko), both produced by Vertex Pharmaceuticals.

Class 3: impaired gating

Another type of mutation can result in the production of a CFTR protein that makes it to the cell membrane but does not open correctly. This is often referred to as a “gating defect.”

Gly551Asp, Ser549Arg, and Gly1349Asp are examples of mutations causing gating defects.

Treatments called CFTR potentiators, such as Kalydeco, can be used to open the channels and/or keep them open for longer.

Class 4: decreased conductance

The fourth class of mutation results in a CFTR protein that makes it to the cell membrane and reacts to cell signaling to open, but the protein is misshapen and only allows a small amount of chloride ions to pass through. This reduction in chloride ion movement is called decreased conductance.

Examples of such mutations include Arg117His, Arg334Trp, and Ala455Glu.

CFTR potentiators can also be helpful for these mutations to keep the channels open for longer to allow more chloride ions to flow through.

Class 5: less protein

Sometimes a mutation can lead to CFTR protein being produced but just not in sufficient amounts. This is often caused by a process called alternative splicing in which correct versions of the protein are sometimes made but more often incorrect versions are produced. The incorrect versions never make it to the cell surface, which leads to a reduction in the number of CFTR protein channels at the cell membrane.

Class 5 mutations include 3272-26A→G, 3849+10 kg C→T.

Possible treatments for this type of mutation include CFTR correctors to correct the misshapen CFTR proteins, CFTR potentiators to try and keep the working CFTR proteins open for longer, CFTR amplifiers to increase the amount of mRNA and therefore more CFTR protein being produced, or antisense oligonucleotides, which can have a number of different uses.

Class 6: less stable protein

The final type of mutation can result in a working CFTR protein but the protein configuration is not stable and will degrade too quickly once on the cell surface.

Class 6 mutations include c. 120del123 and rPhe580del.

Stabilizers are a class of treatment for this type of mutation. They work to inhibit enzymes that break down CFTR. A treatment called cavosonstat was being investigated for this use but failed to meet primary objectives in a Phase 2 clinical trial.


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