Scientists have found new genetic causes for diabetes in babies – in a part of the genome that has historically been overlooked in genetic studies.
Until recently, most research has investigated causes of disease in 'coding' genes – those that produce proteins. Now, academics at the University of Exeter and their international collaborators have found that DNA changes in two genes that instead make functional RNA molecules are a cause of diabetes. RNA plays various roles in the body, including regulating genes and influencing how genetic information is "read" and interpreted.
In work supported by the National Institute for Health and Care Research (NIHR Exeter Biomedical Research Centre and the Exeter NIHR Clinical Research Facility, the team used genome sequencing, a method that reads all the letters in a person's DNA. They found that changes in two genes called RNU4ATAC and RNU6ATAC were the cause of autoimmune neonatal diabetes in 19 children. The children in the study were identified through the University of Exeter's work in offering free genetic testing to children thought to have genetic forms of diabetes across the world.
Neonatal diabetes is a rare form of diabetes that occurs within the first six months of life and is caused by genetic changes. Understanding the cause unlocks the potential for new treatments and better care. The research also helps give more insight into the possible causes of rare disease, which affects one in 17 people.
Study lead Associate Professor Elisa De Franco, of the University of Exeter Medical School, said "For the first time, we found that DNA changes in non-protein coding genes cause neonatal diabetes. This shows the importance of non-protein coding genes and their potential to cause disease in humans. With up to half of individuals with rare diseases currently living without a diagnosis, exploring the non-coding DNA can provide answers for families with rare conditions"
The researchers found that the 19 children all had an autoimmune form of diabetes, in which the immune system attacks insulin-producing beta cells that regulate blood sugar. This also occurs in type 1 diabetes. The team used state-of-the-art laboratory and computational methods to analyse the children's samples and found that the mutation in the two non-coding genes was causing disruption to around 800 other genes, many linked to the immune system.
Dr James Russ-Silsby, of the University of Exeter, co-first author of the study, said: 'Combining the DNA sequencing results with detailed analyses of the patients' blood samples gave us a much deeper view of how these DNA changes play out inside the cell. This is helping us understand how these DNA changes result in diabetes."
Dr Matthew Johnson, Senior Research Fellow at the University of Exeter and co-first author of the study, said "This finding is important as highlights that one or more of these 800 genes has a central role in the development of autoimmune diabetes, and could uncover new biology and potential drug targets for more common type 1 diabetes.
"Whilst the condition caused by these genetic changes is rare, it provides us with unique opportunities to study the pathways that lead to autoimmune forms of diabetes in humans, giving us a window into the ways type 1 diabetes can develop".
The study is titled ' Bi-allelic variants in the non-protein-coding minor spliceosome components RNU6ATAC and RNU4ATAC cause syndromic monogenic autoimmune diabetes' , and was published in the American Journal of Human Genetics. and will be presented by Dr James Russ-Silsby at the conference of the European Society of Human Genetics conference in Sweden in June.
