PhD student James Russ-Silsby is based in the Exeter Medical School diabetes group and is studying monogenetic diabetes. James’s lead supervisor is Dr Elisa De-Franco.
As we observe World Diabetes Day, I am proud to share some of the amazing research our team at Exeter has conducted on the genetics of neonatal diabetes, a very rare form of diabetes that affects newborns and infants at a rate of approximately 1 in 100,000 births. Unlike the more common types 1 and 2 diabetes, neonatal diabetes is caused by a genetic defect affecting a single gene, making it a monogenic disorder. To date, 36 different causes of neonatal diabetes have been described, explaining around 85% of cases. As one of the leading teams on neonatal diabetes research, we have access to the largest patient cohort in the world, with more than 3000 individuals rereferred from over 110 different countries. This fantastic resource gives us a unique ability to study even the rarest genetic causes of the disease.
Improving patient outcomes
By understanding the causes of neonatal diabetes, we can improve patient outcomes through clinical management, informed genetic counselling, and potentially more targeted treatments. One of the most famous historical examples of this was the discovery by the Exeter team of the KCNJ11 and ABCC8 potassium channel subunit encoding genes as causes of neonatal diabetes. The form of the disease that results from variants in these genes can be treated with oral sulfonylureas, which restore the function of the potassium channel and help manage glucose levels more effectively and less invasively. This discovery is an excellent example of how research can directly benefit patients.
Discovering roles of neonatal diabetes genes
Furthermore, because the genes involved in neonatal diabetes typically have essential roles in beta cell function and/or development, discovering new causes of the disease can provide valuable insights into these processes. Through the study of neonatal diabetes, we have gained critical insights into how developmental transcription factor genes like GATA6, GATA4, and CNOT1 work to control the formation of the foetal pancreas. Additionally, we have learned how immature pancreatic cells are differentiated into mature insulin-producing pancreatic beta cells by later-stage transcription factors like NEUROD1, NEUROG3 and NKX2-2. Finally, we have understood how endoplasmic reticulum stress response genes like PDIA6 and FICD enable beta cells to survive exposure to stressors. Understanding these cellular processes is key to our understanding of beta cell function and is a step towards improving patient care and identifying new treatment options for all forms of diabetes.
A recent success story of the team is the discovery of the ZNF808 gene as a novel cause of neonatal diabetes. This discovery not only led to the identification of a new disease mechanism, but it is also the first documented case of the loss of a primate-specific gene causing Mendelian disease. ZNF808 is part of the rapidly evolving KRAB zinc finger family of DNA binding proteins. These proteins exist in a perpetual arms race with the equally fast-evolving transposable elements, with their primary function being to inhibit the replication of these potentially damaging mobile sequences. Since the gene’s discovery, we have identified more than 25 individuals with genetic variants in ZNF808 as the cause of their diabetes. We are now working on a follow-up paper in which we examine variation in disease expressivity among this larger cohort of individuals with ZNF808-caused diabetes.
One of the key reasons for our success at Exeter is the multifaceted approach we take to research. In addition to the examination of our patient cohort for gene discovery, we use functional approaches, such as transcriptomics, to gain further insights into the role of a gene. We also make use of large publicly available population cohorts to assess the role of neonatal diabetes genes in more common forms of diabetes. A great example of this is a recent study where we used the UK Biobank to identify an association between genetic variants that result in a loss of function of the ONECUT1 gene and type 2 diabetes. We are also strong believers in the power of scientific collaboration and have many ongoing collaborations at universities around the world. These collaborations with other researchers enable us to conduct experiments to evaluate neonatal diabetes genes that we could not perform independently.
As I near the end of my second year, I feel incredibly privileged to be conducting my PhD as part of the Exeter neonatal diabetes research team and am proud that I get to contribute to the amazing research that comes out of it.