A defect has been identified in the gene MAFA

Gene linked to opposing blood sugar conditions in single family

Scientists from the University of Exeter Medical Schoolhave uncovered new insights into the genomics of diabetes through the rare case of a family where one gene is associated with two opposing conditions.

A collaboration between the University of Exeter Medical School, Queen Mary University of London and Vanderbilt University investigated several individuals in a family who have diabetes. Others in the same family had developed multiple insulin-producing tumours in their pancreas. These tumours, known as insulinomas, typically cause low blood sugar levels, in contrast to diabetes which leads to high blood sugar levels.

The researchers identified a genetic variant in a gene called MAFA, which controls the production of insulin in beta cells, which are found in the pancreas. Unexpectedly, the gene variant was found in both the family members with the diabetes and those with insulinomas, and was also identified in a second, unrelated family with the same unusual dual picture.

This is the first time the gene MAFA has been associated with a disease, and these findings demonstrate how the same genetic disorder can cause opposing conditions within the same family. Studies on rare diseases such as these are crucial in aiding our understanding of diabetes. 

Dr Donato Iacovazzo, the first author of the paper added: “We believe this gene defect is critical in the development of the disease and we are now performing further studies to determine how this defect can, on the one hand, impair the production of insulin to cause diabetes, and on the other, cause insulinomas.”

Dr Sarah Flanagan, from the University of Exeter, said: “We were initially surprised about the association of two apparently contrasting conditions within the same families. These contrasting manifestations are probably due to other factors. For example, we observed that males were more prone to develop diabetes, while insulinomas were more commonly found in females, but the reasons behind this difference are as yet unknown. We want to look into understanding the mechanism by which this one mutation can lead to opposite effects.”

Professor Sian Ellard, the Exeter team leader, said: “While the disease we have characterised is very rare, studying rare conditions helps us understand more about the physiology and the mechanisms underlying more common diseases. We hope that in the longer term this research will lead to us exploring new ways to trigger the regeneration of beta cells to treat more common forms of diabetes. 

The study was funded by Diabetes UK, the Wellcome Trust and Royal Society. The research, MAFA missense mutation causes familial insulinomatosis and diabetes mellitus, is published in the journal Proceedings of the National Academy of Sciences of United States of America (PNAS).

Faye Riley is Research Communications Officer at Diabetes UK. She said: “At Diabetes UK, we’re committed to understanding more about the causes of all types of diabetes. This research gives us important insights into the impact a change in this particular gene has on insulin-producing beta cells and how this relates to the development of a rare genetic form of diabetes. It’s also a great example of how studying rarer conditions could help us learn more about more common types of diabetes.”

Date: 5 January 2018