Gene mutation contributes to diabetes

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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, writes Wai Lang Chu..

The discovery bodes well for future understanding of the disorder as well as the design and execution of an intervention strategy, possibly in the form of a drug or gene therapy.

Like its lifestyle-related counterpart, type 2 diabetes, the incidence of type 1 has increased dramatically - a near 300 per cent increase in the last 20 years. While a host of factors have been attributed to this rise, scientists have yet to discover the primary cause.

This discovery is a step closer to establishing the cause of diabetes on a genetic level. Type 1 diabetes is an autoimmune disease. This is where immune responses are directed towards the body's own structures, here in type 1 diabetes leucocytes "attack" beta cells in the pancreas, and destroy them. The insulin producing capacity thus decreases to a level that does not meet the demands of the glucose metabolism

Dr Cong-Yi Wang, molecular geneticist and co-senior author of the study told:"Type 1 diabetes is a complicated disorder occurring from the influence of multiple genes. We are finding an increase in newborn babies diagnosed with this as well as in adults."

"It is a combination of factors that include diet and environmental. We can't say for sure. Type 2 diabetes is closely linked with obesity for example."

The newly discovered gene, SUMO-4, was found to control the activity of NFkappaB, a molecule that in turn controls the activity of cytokines, proteins that regulate the intensity and duration of the immune response.

They found the SUMO-4 mutation overrides the system that controls cytokine production In addition to the increase the initiated immune response is directed to the insulin beta cells of the pancreas.

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

Dr Jin-Xiong She, director of the MCG Centre for Biotechnology and Genomic Medicine and a co-senior author of the study said: "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."

Wang said: "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."

The team found that an environmental trigger such as a bacterial or viral infection was enough to induce that mutation, upsetting the balance of the immune system. The effect is such that an autoimmune response is initiated that attacks the patient's own tissue.

Dr She said: "SUMO-4 is the fourth gene identified that contributes to type 1 diabetes, taking a place just behind the human leukocyte antigen (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."

Wang added: "This discovery provides us with a therapeutic target which not only provides a basis for treatment but the potential for developing a cure."

Pinpointing a gene involved in a complex disease such as diabetes is a relatively new approach after having been attempted only a handful of times previously. The technique employed by the researchers involved looking at those genes most often transmitted to children with diabetes.

Dr. She said: "You guess the function, you guess the disease possibilities, then you guess which genes might be involved in the pathogenesis."

"As a community, we have guessed right a few times, including identification of HLA. But this is the first time we have used a systematic approach to find the gene and it's the first gene in which we know how it contributes to the disease."

The HLA is known to be a regulator of immunity but researchers still don't know exactly how it causes diabetes. The MCG team found that SUMO-4 encodes a protein that modifies the activity of NfkappaB. Whilst it was common knowledge that NFkappaB regulated the production of certain cytokines involved in type 1 diabetes it was still unclear as to the cause of the excessive cytokine production observed in the disease.

The research will be published in the August print issue of Nature Genetics​ and online July 11 and represents only the start of their research. The MCG team have begun to explore the gene's potential role in other autoimmune diseases as well such as lupus, thyroid disease, arthritis and multiple sclerosis.

Wang also added: At the moment we have a US patent pending on this discovery. We have also had interest from drug companies who are keen on developing this further."

Related topics: Preclinical Research

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