Research brings greater understanding of cystic fibrosis genes

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The Cystic Fibrosis Trust has part-funded research that provides new understanding of ‘silent changes’ in the cystic fibrosis (CF) gene, which has been publish in PLoS Biology.

Professor Zoya Ignatova (University of Hamburg), Professor David Sheppard (University of Bristol) and their team have published research demonstrating a major advance in our understanding of ‘silent’ changes in the faulty CF gene, with implications for understanding individual to individual variability in cystic fibrosis.

Their work was published in PLoS Biology, a high-profile, peer-reviewed scientific journal, yesterday.


Genes and proteins

Cystic fibrosis is caused by a faulty gene that causes a protein called CFTR to become disabled or be destroyed. CFTR plays a crucial role in cells lining ducts and tubes by forming a gated pathway for chloride ions, one part of salt, to stream across cell membranes. When this protein is missing or does not work properly, mucus builds up in the affected organs.

An individual has CF when they inherit two faults in the CFTR gene, one from each parent. These two faults can be the same, or they could be two different changes in the CFTR gene. The severity of CF varies between any two individuals. In part, differences in severity result from how different genetic faults affect how the CFTR protein is made and how it works in cells. 

Silent changes

Scientists have identified more than 2,000 changes in the gene controlling how CFTR is made and how it works in cells. Around 1,700 of these changes are faults that cause cystic fibrosis. The other 300 include a group of ‘silent changes’, so-called because the gene is different, but these differences don’t seem to have any effect on the composition of the protein. These silent changes are not considered to cause cystic fibrosis. 

The research findings

Professor Ignatova and Professor Sheppard worked with Professor Ineke Braakman, Utrecht Univeristy and Dr Lynda Ostedgaard, University of Iowa, to investigate how one such silent change in the CFTR gene, called T2562G, affects the CFTR protein. 

T2562G changes how the CFTR protein is made by cells. At the University of Bristol, Dr Zhiwei Cai discovered that T2562G causes the CFTR pathway for chloride ions to become narrowed, slowing chloride movement across cell membranes. 

At the University of Hamburg, Dr-Sebastian Kirchner and Robert Rauscher found that the change in how CFTR is made is the result of how the cell reads genetic information. T2562G causes the cell to produce CFTR more slowly, resulting in an altered protein with impaired chloride transport. This finding reveals a new unexpected way by which silent changes in genes alter how proteins are made and how they work in cells.

This new research shows that how CFTR is made and how it works is additionally influenced by changes in the CFTR gene that are not CF-causing. When these changes occur together with CF-causing faults, they will affect the severity of the condition and an individual’s response to treatment targeting the root cause of it. The research also highlights the way teams of scientists working in different countries are able to collaborate to make advances in our understanding of cystic fibrosis.

Professor Sheppard said: "I'm delighted to see this paper published. It has been absolutely fascinating to investigate the silent change in the CFTR gene called T2562G. This paper is a great example of CF researchers from different labs working together to understand the genetic complexity of the disease. The paper is definitely greater than the sum of the different parts."

Read the paper

Looking forward

Research like this helps pave the way for the next big breakthrough. Professors Ignatova, Sheppard and their team have contributed new understanding about the genetics of cystic fibrosis. Other researchers will be able to build on this progress in future.

When is a cake bake not just a cake bake? When it funds groundbreaking research! By organising your own fundraising event, you can raise money to pay for research like this and help beat cystic fibrosis for good. 

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