New gene associated with type 1 diabetes

July 22, 2004

HOUSTON — A new gene mutation identified by researchers at Baylor College of Medicine (BCM) in Houston is part of the constellation of genes associated with susceptibility to developing type 1 diabetes. It could also play a role in the devastating complications of diabetes such as kidney failure.

The gene called SUMO-4 contributes a portion of the risk of getting this form of diabetes, which typically strikes youngsters, said Drs. David Owerbach, Kurt Bohren and Kenneth Gabbay. Owerbach and Bohren are associate and assistant professors in the section of molecular diabetes and metabolism in the department of pediatrics at BCM, respectively. Gabbay is professor of pediatrics and head of the section.

SUMO-4 plays a role in regulating the immune system. When mutated, the gene functions abnormally, prolonging the inflammatory response.

This finding gives scientists a clue about the autoimmune cause of diabetes. In type 1 diabetes, the body's protective system is turned against its own insulin-producing alpha cells in the pancreas. As a result, people who have type 1 diabetes do not produce insulin. Without insulin, their bodies cannot regulate the levels of sugar in their blood.

The mutated SUMO-4 gene may influence the inflammatory process itself and increase the susceptibility to the complications of diabetes.

The reports of the work by Owerbach, Bohren and Gabbay and the rest of their team in the Harry B. and Aileen B. Gordon Diabetes Research Center at Texas Children's Hospital and BCM appeared in the June 25, 2004 issue of the Journal of Biological Chemistry and the July 2004 issue of the journal Diabetes.

No single gene causes type 1 diabetes. However, the BCM researchers and others in the field have identified a host of genes that contribute to the risk of developing the disease. Among the most potent genes are those in the HLA or human leukocyte antigen region, which regulate the immune system and help immune cells differentiate self from non-self.

Gene variants of DR and DQ in the HLA region are particularly important and are found in 95 percent of type 1 diabetics. Together, the genes in the HLA region account for as much as 40 percent of the familial risk of developing type1 diabetes. A second set of Type 1 diabetes susceptibility genes have also been identified in the region immediately preceding the insulin gene. This region contains a VNTR or variable number of tandem repeats, which refers to repeats of specific chemical bases that make up DNA. Inheritance of certain VNTR's increases the risk of developing type 1 diabetes.

SUMO-4 contributes to the overall risk. However, the significance of the SUMO-4 gene lies in its role in controlling the immune and inflammatory response. The diabetes-associated variant gene appears to increase the stress response and cell death. SUMO-4 may provide a therapeutic target to modify or curtail the inflammatory process leading to the destruction of the alpha cells.
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A group from the Medical College of George recently independently confirmed the BCM findings in a report that appears online in Nature Genetics and will be published in August.

This research that led to the identification of SUMO-4 was funded by the Juvenile Diabetes Foundation and the Harry B. and Aileen B. Gordon Foundation.

Baylor College of Medicine

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