**Mutations to the CFTR gene – how do they cause cystic fibrosis?**

By Jade Ashton

The cystic fibrosis transmembrane conductance regulator (CFTR)

Whether you’re new to cystic fibrosis (CF) or want to get a better understanding of your condition, this article should teach you something new. We cover how CF is inherited and the different types of mutation that can cause it.

It’s best to read this article from start to finish. Here are the different parts of the article:

Genes – instructions that help cells do their job
The cystic fibrosis transmembrane conductance regulator (CFTR)
Inheriting CF
What happens to CFTR doorways when there are CFTR gene mutations
Ways of grouping CFTR mutations

Cystic fibrosis (CF) is a lifelong inherited condition. Around 50,000 people live with CF in Europe, but the entire CF community is much larger – family, friends, healthcare teams and researchers are all working towards a longer and better life for those with the condition.

You can read more about what living with CF is like here.

A guided tour to the airway

The cystic fibrosis transmembrane conductance regulator (CFTR)

CF happens because of changes in a gene called CFTR, or the cystic fibrosis transmembrane conductance regulator gene. The CFTR gene contains the instructions for making the CFTR protein.

From gene to protein

The CFTR protein is a type of cell channel or doorway. All cells have thousands of different types of tiny doorways on their surface. Different doorways let different molecules move in and out of cells. This is a normal part of how the human body works. The job of the CFTR protein doorway is to let chloride (a component of salt) out of cells. CFTR doorways are only found in some cells of the body, such as the cells lining the airway and the gut.

How CFTR doorways should work

When CFTR doorways are faulty, chloride cannot exit these cells properly. This upsets the balance of water and causes many issues. For example, people with CF can have thick sticky mucus in the airways and they can struggle to digest food.

CFTR in cystic fibrosis

Inheriting CF

Everyone has two CFTR genes, one from each of their parents. Someone is born with CF when the two CFTR genes they inherit both have mutations. The two CFTR gene mutations can be the same or different from each other.

Inheriting just one CFTR gene with a mutation and one unchanged CFTR gene makes you a ‘carrier’ of CF. Carriers do not have CF and do not need any CF treatment. Most of the time, people do not know that they are carriers.

What happens to CFTR doorways when there are CFTR gene mutations?

Over 2,000 CFTR gene mutations have been discovered so far, but only around 380 stop the CFTR doorway from working properly, causing CF. Some mutations stop the doorway from working more than others. This is because different things can happen when the cell machinery uses faulty instructions to make the CFTR doorway.

CFTR gene mutations that cause CF impact the CFTR doorway in one of two ways:

1) The CFTR doorway is not finished

Signals at the beginning and end of a gene tell the cell machinery when to start and stop reading the instructions. Some faulty gene instructions add extra ‘stop’ signals in the gene. These are called nonsense mutations. Genes with nonsense mutations instruct cells to produce unfinished CFTR doorways. Unfinished doorways do not work at all and are recycled by the cell.
Genes are split up into chunks with breaks in between them like a Toblerone®. Sometimes cells can make different proteins from the same genes by cutting and stitching together different combinations of chunks to get new instructions. This is called splicing. It is a normal part of how cells work. The beginning and end of each block also have a ‘start’ and ‘stop’ signal. If a mutation puts these signals in the wrong place, the length of the chunks can change. The cell machinery can cut and stitch the wrong chunks together, completely changing the CFTR doorway. Some mutations allow the cell to still cut and stitch the correct chunks together, but only some of the time. This means not enough full CFTR doorways are made. These changes are called splicing mutations.
Some mutations confuse how the cell machinery reads the gene instructions. These frameshift mutations mean that the cellular machinery cannot understand the instructions and produces a protein that looks nothing like a CFTR doorway.

2) The CFTR doorway is the wrong shape

Some faulty gene instructions lead to protein building blocks (called amino acids) being missed, added, or swapped for another. This can change the shape of the CFTR doorway. Sometimes this leads to it being broken down and recycled by the cell’s quality control machinery. Sometimes the CFTR doorway ends up in the right place at the cell surface, but its faulty shape means it cannot open properly. Other changes mean that chloride cannot flow through the doorway easily, or the doorway is unstable and breaks down quickly. Some changes mean a combination of these faults can happen.

Ways of grouping CFTR mutations

The ways that scientists group CFTR gene mutations has changed as we continue to research and better understand CF.

A broad way of grouping CFTR gene mutations uses these three categories:

Minimal function mutations
Genes with minimal function mutations instruct cells to make CFTR protein doorways that do not work, or only work a little. The doorways could be the wrong shape, or they could be unfinished because of nonsense, frameshift or splicing mutations.
Gating mutations
Genes with gating mutations instruct cells to make CFTR protein doorways that are mostly locked shut. The doorways could be the wrong shape, or they could be unfinished because of a splicing mutation.
Residual function mutations
Genes with residual function mutations instruct cells to make fewer or faulty CFTR doorways. The CFTR doorways work a little bit. The doorways could be the wrong shape, or they could be unfinished because of a splicing mutation.

A more traditional way of grouping CFTR gene mutations is with Classes I to VI. Here’s how they relate to the classes above. Knowing these classes can help us understand why certain modulator medications work for some people with CF and not for others.

A guided tour of CFTR mutations