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Georgia Team Links Another Mutation to Type 1 Diabetes

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A mutation that helps regulate immune system reactivity may be a “major contributor” to type 1 diabetes, according to researchers at the Medical College of Georgia.

The gene, SUMO-4, is known to control NFkB, a molecule that oversees cytokine activity. The mutation is a substitution (M55V) at an evolutionarilyy conserved residue in the CUE domain. The researchers, led by Jin-Xiong She, examined parents and their children in 944 diabetic families from various nationalities and believe this substitution is associated with an increased risk of developing type 1 diabetes.

The discovery may lead to a molecular diagnostic for the disease, whose incidence has grown more than 300 percent over the past 20 years, according to the researchers.

“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,” Jin-Xiong She, director of the MCG Center for Biotechnology and Genomic Medicine and a co-senior author on the study, said in a statement.

Cong-Yi Wang, a molecular geneticist at MCG and co-senior author of the study, added that the mutation will “increase the responsive capacity of the immune system to environmental triggers or stimulators; it makes it more reactive.”

Studying their data, the researchers found that when that mutation encounters an environmental trigger — a bacterial or viral infection, for example — it “throws off the usual well-balanced activity of the immune system” and triggers an autoimmune response.

Their study appears in the August print issue of Nature Genetics.

To be sure, the mutation represents the fourth gene identified so far that is believed to play a role in type 1 diabetes. However, “this is one of the most important ones,” said She (pronounced SHU).

His research allowed him to follow diabetic families in Florida and Georgia in hopes of identifying the links between genes, the immune system, and the environment that may contribute to the disease.

The MCG team found that SUMO-4 encodes a protein that modifies the activity of NFkB. It has already been known that NFkB regulates the production of certain cytokines, and that cytokines play 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,” the scientists said. She’s findings helped the researcher figure out 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 “overrides the systems that put cytokine production on autopilot or shut it down,” the team wrote in the statement. “Instead, it enables cytokine production not only to increase but directs the increased immune response at the insulin-producing beta cells of the pancreas.”

—KL

 

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