A gene mutation seen for the first time worldwide in two siblings has helped scientists further their understanding of the development of diabetes.

It began when the siblings were diagnosed with a rare form of diabetes in their first few weeks of life. Early childhood diabetes is rare, and is thought to be the result of a variety of genetic variations.

For babies diagnosed with the condition before they are nine months old, the University of Exeter offers a genetic testing service. Around 50% of babies who undergo the testing have their treatment pathway amended.

However, when the two siblings were tested, scientists could not identify any mutation in any of the known causes.

They extended their testing and performed whole genome sequencing in a bid to identify previously unknown causes of autoimmune diabetes.

By taking this approach the team discovered a mutation in the gene encoding PD-L1 which could be responsible for their very early onset autoimmune diabetes.

Study author Dr Matthew Johnson, from the University of Exeter, commented: “To our knowledge, nobody has ever found humans with a disease-causing mutation in the gene encoding PD-L1. 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.

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

Researchers from the University of Exeter joined forces with colleagues from the Rockefeller Institute in New York and King’s College London to study the siblings, with funding provided by Wellcome, The Leona M. and Harry B. Helmsley Charitable Trust, Diabetes UK, and the US National Institutes for Health.

Samples were collected from the siblings and taken to King’s College London, where the London and New York teams carried out comprehensive analysis on cells.

Study co-author Dr Masato Ogishi, from the Rockefeller University in New York, said: “We first showed that the mutation completely disabled the function of PD-L1 protein. We then studied the immune system of the siblings to look for immunological abnormalities that could account for their extremely early-onset diabetes.

“As we previously described another two siblings with PD-1 deficiency, both of whom had multi-organ autoimmunity including autoimmune diabetes and extensive dysregulation in their immune cells, we expected to find severe dysregulation of the immune system in the PD-L1-deficient siblings.

“To our great surprise, their immune systems looked pretty much normal in almost all aspects throughout the study. Therefore, PD-L1 is certainly indispensable for preventing autoimmune diabetes but is dispensable for many other aspects of human immune system. “We think that PD-L2, another ligand of PD-1, albeit less well-studied than PD-L1, may be serving as a back-up system when PD-L1 is not available. This concept needs to be further investigated in the context of artificial blockade for PD-L1 as cancer immunotherapy.”

Study co-author Professor Timothy Tree, from King’s College London, said: “Through studying this one set of siblings – unique in the world to our knowledge – we have found that the PD-L1 gene is essential for avoiding autoimmune diabetes, but is not essential for ‘everyday’ immune function. This leads us to the grand question; ‘what is the role of PD-L1 in our pancreas making it critical for preventing our immune cells destroying our beta cells?’

“We know that under certain conditions beta cells express PD-L1. However, certain types of immune cells in the pancreas also express PD-L1. We now need to work out the “communication” between different cell types that is critical for preventing autoimmune diabetes.

“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.

“Simultaneously, it gives new knowledge to the cancer immunotherapy field by uniquely providing the results of completely disabling PD-L1 in a person, something you could never manipulate in studies. Reducing PD-L1 is already effective for cancer treatment, and boosting it is now being investigated as a type 1 diabetes treatment – our findings will help accelerate the search for new and better drugs.”

The study has been published in JEM.

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