Scientists discover new genetic cause of diabetes in infants

Scientists have discovered a new genetic cause of diabetes in infants – in a part of the genome that has historically been overlooked in genetic studies.

Until recently, most research has examined the causes of disease in ‘coding’ genes – those that produce proteins. Now, academics at the University of Exeter and their international colleagues have found that DNA changes in two genes that instead make functional RNA molecules are the cause of diabetes. RNA plays a variety of roles in the body, including regulating genes and influencing the way genetic information is “read” and interpreted.

In work supported by the National Institute for Health and Care Research (NIHR Exeter Biomedical Research Center and 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 mutations 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 work at the University of Exeter. Free genetic testing is being offered to children genetically predisposed to diabetes around 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 opens the possibility for new treatments and better care. The research also helps shed more light on the possible causes of the rare disease, which affects one in 17 people.

Study leader 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 demonstrates the importance of non-protein coding genes and their potential to cause disease in humans. With more than half of individuals with rare diseases currently living without a diagnosis, the discovery of non-coding DNA could provide answers for families with rare conditions”

The researchers found that all 19 children had an autoimmune form of diabetes, in which the immune system attacks the insulin-producing beta cells that regulate blood sugar. This also occurs in type 1 diabetes. The team used cutting-edge laboratory and computational methods to analyze the children’s samples and found that the mutation in two non-coding genes was causing disruption in nearly 800 other genes, many of which were associated with the immune system.

Combining the DNA sequencing results with detailed analysis of patients’ blood samples gave us a more in-depth understanding of how these DNA changes occur inside the cell. “This is helping us understand how these DNA changes result in diabetes.”

Dr. James Russ-Silsby, of the University of Exeter, is co-first author of the study

Dr Matthew Johnson, Senior Research Fellow at the University of Exeter and co-first author of the study, said: “This discovery is important because it highlights that one or more of these 800 genes have a central role in the development of autoimmune diabetes, and may uncover new biology and potential drug targets for the more common type 1 diabetes.

“Although the condition caused by these genetic changes is rare, it provides us with unique opportunities to study the pathways that cause autoimmune forms of diabetes in humans, giving us insight into the ways in which type 1 diabetes develops”.

The study is titled ‘Bi-allelic variants in non-protein-coding minor spliceosome components’ RNU6ATAC And RNU4ATAC ‘A cause of 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 European Society of Human Genetics conference in Sweden in June.