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Breakthrough: Rare Gene Mutation Offers Clues to Preventing Type 1 Diabetes

Breakthrough: Rare Gene Mutation Offers Clues to Preventing Type 1 Diabetes


Posted on April 30, 2024 Updated on April 27, 2024

A unique genetic mutation in two siblings – that has never been seen in anyone else – has been discovered by UK researchers at the University of Exeter, pointing the way towards new treatment options for type 1 diabetes.

The mutation is in the gene for a protein called programmed death-ligand 1 (PD-L1), and a new study explains how it may be responsible for the autoimmune form of diabetes that the children developed at a very young age.

“We searched the globe, looking at all the large-scale datasets that we know of, and we haven’t been able to find another family,” says molecular geneticist Matthew Johnson, from the University of Exeter in the UK.

“These siblings therefore provide us with a unique and incredibly important opportunity to investigate what happens when this gene is disabled in humans.”

Type 1 diabetes is also known as autoimmune diabetes because of the way the body’s built-in immune system defense attacks pancreatic beta cells, stopping normal insulin production. People with the condition have to regularly inject insulin to manage their blood sugar levels.

The siblings, aged 10 and 11 at the time of the study, developed diabetes in the first weeks of their lives. A closer analysis of immune cells from the siblings confirmed that their unique genetic mutation prevented the PD-L1 protein from working properly.

As PD-L1 and its PD-1 receptor combine as a sort of safety mechanism to keep the immune system in check, and cancer treatments that block PD-L1 functions can also lead to diabetes developing, it looks like PD-L1 is crucial in stopping type 1 diabetes from starting.

However, in a surprising twist, it turned out that the immune systems of the two young siblings were operating pretty much as normal, even without the immune system regulation that PD-L1 and PD-1 normally provide.

“We think that PD-L2, another ligand of PD-1, albeit less well-studied than PD-L1, may be serving as a backup system when PD-L1 is not available,” says physician-scientist Masato Ogishi from the Rockefeller University in New York.

One key conclusion the researchers arrived at is that the PL-D1 protein is crucial in preventing type 1 diabetes, but isn’t crucial for keeping many of the other immune system functions running as normal.

The clues provided by the genetic mutation, plus the cancer treatment and diabetes link, could help to unlock new ways of tackling the onset of type 1 diabetes – if researchers can figure out how PD-L1 prevents it, and how PD-L2 acts as a backup.

“We now need to work out the communication between different cell types that is critical for preventing autoimmune diabetes,” says immunologist Timothy Tree from King’s College London in the UK.

“This finding increases our knowledge of how autoimmune forms of diabetes such as type 1 diabetes develop. It opens up a new potential target for treatments that could prevent diabetes in the future.”

The research has been published in the Journal of Experimental Medicine.

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