Types of CFTR Mutations

Some genetic diseases, such as cystic fibrosis, are caused by mutations in a single gene. A gene contains DNA “letters” that spell out the instructions to make a specific protein. When the protein isn't made correctly, it can lead to a cascade of problems.

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Summary
  • There are five classes of CFTR mutations: protein production, protein processing, gating, conduction, and insufficient protein.
  • The most common CF mutation, F508del, is primarily considered to be a protein processing mutation.
  • CFTR modulators address various problems caused by different types of CFTR mutations.

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 webcast (starting at 3:03) to see how a nonsense mutation affects production of the CFTR protein and how the mutation might be corrected to make normal 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), and 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 RNA instructions containing the irrelevant letters, or missing relevant ones, it will be unable to build a correct CFTR protein.

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.

The drug combination Trikafta® (elexacaftor/tezacaftor/ivacaftor) works by enabling CFTR protein with an F508del mutation to fold in a more correct shape, and then activates the protein to allow more chloride to pass through. Although this drug combination is not a perfect fix, it helps the mutant CFTR protein to move some chloride. This movement of chloride reduces the symptoms of CF.

Watch the webcast (starting at 3:02) to learn more about CF protein processing mutations and how drugs such as CFTR modulators can help a person with one of these mutations.

Researchers are working on more effective drugs that can fold the protein into a more normal shape, move more chloride out of the cell, and reduce symptoms even further.

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 the webcast (starting at 3:02) to learn more about CF gating mutations and how drugs, such as CFTR modulators, can help a person with one of these mutations.

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.

Watch the webcast (starting at 3:00) to learn more about CF conduction mutations and how a drug such as a CFTR modulator might help a person with one of these mutations.

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 mutations, including missense and splice mutations.

As mentioned above, some splice mutations interfere with the way the cell reads the DNA instructions for making a protein. This can result in a limited quantity of normal CFTR protein reaching the cell surface, which results in residual function.

The FDA approved Kalydeco for five splice mutations in 2017 [and later Symdeko® (tezacaftor/ivacaftor) in 2020]. People with these mutations make a small amount of normal CFTR. Ivacaftor in both Kalydeco and Symdeko 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

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Reference to any specific product, process, or service does not necessarily constitute or imply its endorsement, recommendation or favoring by the Cystic Fibrosis Foundation. The appearance of external hyperlinks does not constitute endorsement by the Cystic Fibrosis Foundation of the linked websites, or the information, products, or services contained therein.

Information contained on this site does not cover all possible uses, actions, precautions, side effects, or interactions. This site is not intended as a substitute for treatment advice from a medical professional. Consult your doctor before making any changes to your treatment.

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

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