Cystic fibrosis is caused by mutations, or errors, in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which result in either no CFTR protein being made or a malformed CFTR protein that can't perform its key function in the cell.

Over the years, scientists have used several different ways of grouping these mutations into different classes. The most recent classification system groups mutations by the problems that they cause in the production of the CFTR protein:

• Protein production mutations (Class 1)
• Protein processing mutations (Class 2)
• Gating mutations (Class 3)
• Conduction mutations (Class 4)
• Insufficient protein mutations (Class 5)

Protein Production Mutations

Protein production mutations, which include nonsense and splice mutations, interfere with the production of the CFTR protein.

All proteins, including CFTR, are made of building blocks called amino acids that are linked together into a long chain. The protein-building instructions spelled out in the CFTR gene tell the cell which of the 20 available amino acids to use at each position in the chain. The letters in the gene also spell out a “stop” signal that lets the cell know that it has reached the end of the instructions and can stop making the protein.

If the CFTR gene has a nonsense mutation, the protein-building instructions contain an early stop signal that causes the production of the CFTR protein to stop prematurely. Therefore, the cell begins to build the CFTR protein normally until it reaches the early stop signal. The cell “thinks” that it has reached the end of the instructions and stops production too soon. Because the cell stops reading the instructions before it finishes making the protein, no functional CFTR protein is produced.

Watch this animation to see how a nonsense mutation affects production of the CFTR protein.

Splice mutations interfere with the ability of the cell to correctly read the instructions for making the CFTR protein. In a healthy person, the instructions spelled out in a gene are interrupted by stretches of DNA letters that do not code for protein, like an article in a magazine might be interrupted by ads. The beginning and end of these stretches of irrelevant letters are marked with a special signal. In order to make the protein, the cell copies the DNA letters into a similar alphabet called ribonucleic acid (RNA). The cell then follows the signals to clip out all of the irrelevant letters — as you might clip out the ads. That way, the instructions can be read straight through from start to finish.

A splice mutation changes the signal that tells the cell where the irrelevant letters in the instructions begin or end. When the cell tries to read its RNA copy of the instructions, it no longer can tell where to begin and end reading. As a result, the cell will either leave in some irrelevant letters or remove some relevant ones. When the cell tries to follow the jumbled RNA instructions, it will be unable to build a correct CFTR protein.

Around 6% of people with CF have a combination of two nonsense, splice, or other rare mutations that do not produce any CFTR protein. Because these individuals do not produce CFTR protein, they cannot benefit from CFTR modulator therapies. Researchers are exploring many different approaches to develop treatments for people with nonsense and rare mutations.

Protein Processing Mutations

The CFTR protein is made up of 1,480 amino acids. When the CFTR protein is made using all of the correct amino acids, it forms a stable 3-D shape. It has to be the right shape to transport chloride.

When a mutation causes an amino acid to be deleted or an incorrect amino acid to be added, the CFTR protein cannot form its correct 3-D shape and function properly. These mutations are considered to be protein processing mutations.

The most common CF mutation, F508del, is primarily considered to be a processing mutation. The F508del mutation removes a single amino acid from the CFTR protein. Without this building block, the CFTR protein cannot stay in the correct 3-D shape. The cell recognizes that the protein isn't the right shape and disposes of it.

CFTR modulators are drugs designed to correct problems with CFTR protein. The drug combinations Alyftrek (vanzacaftor/tezacaftor/deutivacaftor) and Trikafta (elexacaftor/tezacaftor/ivacaftor) work by enabling CFTR protein to fold in a more correct shape and then activating the protein to allow more chloride to pass through. Although these drug combinations are not a perfect fix, they help the mutant CFTR protein to move some chloride. This movement of chloride reduces the symptoms of CF.

Watch this animation to see how CFTR modulator drugs restore protein function in people who have the F508del mutation.

In addition to F508del, missense mutations can sometimes cause processing problems and therefore can be considered processing mutations in those cases. Missense mutations occur when a change in DNA letters causes an incorrect amino acid to be incorporated into the CFTR protein. This leads to either a decrease in the quantity of the protein at the cell surface (defective processing) and/or a decrease in the function of the protein (defective gating or conduction).

Gating Mutations

The CFTR protein is shaped like a tunnel, or channel, with a gate. The cell can open the gate when chloride needs to flow through the channel. Otherwise, the gate stays closed.

Gating mutations lock the gate in the closed position so that chloride cannot get through. The drug Kalydeco (ivacaftor) helps people with gating mutations by forcing the gate on the CFTR channel to stay open. This enables chloride to move through the channel and reduces the symptoms of CF.

Watch this animation to see how ivacaftor can restore protein function in people who have the G551D gating mutation.

Conduction Mutations

Sometimes, a change in one of the amino acids of CFTR means that even though the protein makes the right 3-D shape, it doesn't function as well as it should. In order for CFTR to work correctly, chloride has to be able to move quickly and smoothly through the protein's channel. Some mutations change the shape of the inside of the channel so that chloride cannot move through as easily as it should. This kind of mutation is called a conduction mutation.

CFTR modulators can help activate the protein to allow more chloride to move through the channel.

Insufficient Protein Mutations

Insufficient protein mutations result in a reduced amount of normal CFTR protein at the cell surface. This occurs for several reasons: a limited amount of CFTR protein is produced; only a small number of protein at the cell surface works correctly; or normal protein at the cell surface degrades too quickly, leaving small numbers of protein behind.

In each case, insufficient functional proteins at the cell surface produce only some, or residual, function of the chloride channel. Insufficient protein can be caused by several types of mutations, including missense and splice mutations.

CFTR modulators can force the gate on the normal CFTR protein to stay open for longer to compensate for the insufficient protein numbers on the surface of the cell. By staying open longer, more chloride can flow through the channel, which may reduce the symptoms of CF.

Resources on CF Mutations

• Use the CFTR2 database to find out more about your specific mutations.
• The CF Foundation's Mutation Analysis Program offers free genetic testing for people with CF.
• If you have questions about your or your child's CF mutations, speak with your doctor or a genetic counselor. You can find a genetic counselor familiar with CF by contacting a CF Foundation-accredited care center.
• Visit the National Society of Genetic Counselors.

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FDA-approved drug information is available at dailymed.nlm.nih.gov/dailymed.