The SUMO-4 gene and type 1 diabetes 12/7/04. By the Medical College of Georgia A natural mutation of a gene that helps regulate the reactivity of the immune system is a major contributor to type 1 diabetes, researchers have found.

The newly discovered gene, SUMO-4, controls the activity of NFkB, a molecule that in turn controls the activity of cytokines, proteins that regulate the intensity and duration of the immune response, according to research published in the journal Nature Genetics.

By examining the transmission of genes from parents to children in nearly 1000 diabetic families from around the world, researchers at the Medical College of Georgia, USA, found that a certain natural mutation of that SUMO-4 gene increases the risk of type 1diabetes.

Feature: Introduction to diabetes

"This helps us understand how type 1 diabetes works, and we can use this improved understanding to better predict who will get the disease and design new intervention strategies for those who do," said Dr Jin-Xiong She, director of the MCG Center for Biotechnology and Genomic Medicine and a co-senior author on the study.

"The mutation we have found is going to increase the responsive capacity of the immune system to environmental triggers or stimulators; it makes it more reactive," said Dr Cong-Yi Wang, molecular geneticist and co-senior author.

Dr Wang and his research team found that when that mutation encounters an environmental trigger, such as a bacterial or viral infection, it throws off the usual well-balanced activity of the immune system, initiating an autoimmune response that eventually attacks the patient's own tissue.

They already are exploring the gene's potential role in other autoimmune diseases as well such as lupus, thyroid disease, arthritis and multiple sclerosis.

SUMO-4 is the fourth gene identified that contributes to type 1 diabetes, taking a place just behind HLA, another regulator of immunity, in terms of relative risk. "Many genes are involved in type 1 diabetes, but this is one of the most important ones," said Dr She.

HLA is a regulator of immunity that has been known for 30 years, but researchers still don't know exactly how it causes diabetes. The MCG team has found that SUMO-4 encodes a protein that modifies the activity of NFkB. It was already known that NFkB regulates the production of certain cytokines and that cytokines have a role in type 1 diabetes as well as other autoimmune diseases. What wasn't known was the cause of the excessive cytokine production seen in those diseases. Now they know that SUMO-4 regulates the activity of NFkB, which in turn regulates whether cytokine production is on autopilot, shut down or revved up.

The SUMO-4 mutation they found overrides the systems that put cytokine production on autopilot or shut it down. Instead, it enables cytokine production not only to increase but directs the increased immune response at the insulin-producing beta cells of the pancreas.

Adapted from a press release by the Medical College of Georgia.

Further reading

Guo D, et al. (2004) A functional variant of SUMO4, a new IB modifier, is associated with type 1 diabetes. Nature Genetics 11 July, doi:10.1038/ng1391. Abstract