Types of CFTR Mutations

Cystic fibrosis (CF), a progressive genetic disorder that results in the production of thick, sticky mucus in various organs throughout the body, is caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a protein of the same name. Treatments options are determined by the different types of CFTR mutations causing the disease.

To date, nearly 2,000 mutations in the CFTR gene have been identified.

Normally, once the CFTR protein is made, it is shuttled to the cell’s membrane. There, the protein acts like a gate, helping to regulate the flow of chloride ions and water in and out of cells. The proper regulation of this flow is important for the production of mucus; when it is impaired, mucus becomes abnormally thick and sticky.

In CF, this mucus builds up and causes respiratorydigestive, and reproductive problems.

CFTR mutations are generally grouped into different classes based on how they affect the CFTR protein. In general, mutations that result in a more substantial defect in the protein — for example, mutations that prevent any protein from being made at all — are associated with more severe disease.

Because different mutations cause different changes to the protein, they also may affect what treatment options are available for a given individual. For instance, CFTR modulators are a type of medication that can address defects in the CFTR protein caused by specific types of mutations.

No CFTR mRNA or protein

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, which is located right at the start of the gene coding sequence. This enzyme then “reads” the gene to make an intermediate molecule called messenger RNA, or mRNA. Next, this mRNA is sent to the cell’s protein-making machinery, which uses it as a template to ultimately produce a 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 being able to 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. They have been grouped in class IA, one of the more severe forms of the disease.

Nonsense mutations

When a cell’s protein-making machinery “reads” a gene to make a protein, there is a specific sequence in the genetic code, called a stop codon, that signals when the machinery has reached the end of the gene — sort of like how a period denotes the end of a sentence.

A nonsense mutation is a type of mutation that results in a stop codon in the middle of the gene. This causes the production of a shortened version of the CFTR protein, which is then degraded by the cell. Gly542X and Trp1282X are examples of CF-causing nonsense mutations and are in class IB.

Trafficking defects

After the CFTR protein gets made, it needs to be shuttled to the cell’s membrane so it can perform its normal function. Some mutations cause the CFTR protein to misfold, which can prevent it from being transported appropriately.

Examples of this type of mutation (class II) include F508del — the most commom CF-causing mutation — Asn1303Lys, and Ala561Glu. To correct the misfolded proteins and help them reach the cell membrane, treatments called CFTR correctors (which are a type of CFTR modulator) can be used.

Gating defects

The CFTR protein normally works as a gate at the cell’s surface. Some mutations, such as Gly551Asp, Ser549Arg, and Gly1349Asp, lead to the production of a protein for which the gate is “stuck closed.” These mutations are grouped in class III, also one of the more severe disease types.

CFTR potentiators are a type of CFTR modulator that can treat gating defects. These medications help keep the channels open for longer.

In other cases, the gate can 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 and is grouped in class IV, one of the less severe forms of CF. Examples of mutations that cause decreased conductance include Arg117His, Arg334Trp, and Ala455Glu.

Decreased protein production

Sometimes a mutation can lead to CFTR protein being produced, but just not in sufficient amounts working at the cell surface for long enough (class V). This is caused by splicing mutations, which affect the cell’s ability to correctly read CFTR and lead to relevant gene portions being left out. Meanwhile, others that are normally excluded end up as part of the final RNA molecule.

Examples of this mutation type include 3272-26A→G and 3849+10 kg C→T.

Treatment with a CFTR potentiator can be useful in treating mutations of this type, by making the small amount of normal CFTR present at the cell membrane to be open for a longer period.

Decreased protein stability

Some mutations cause the production of a CFTR protein that is functional, but not stable, meaning it will degrade too quickly once on the cell surface. Examples of such mutations, grouped in class VI, include c.120del123 and rF580del (F508del after being rescued by correctors). Class VI also is considered a less-severe disease.


Last updated: July 22, 2021


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