Discovery of gene linked to maturity-onset diabetes of the young

Aug 10 2009

Researchers at the Joslin Diabetes Center have linked another gene to a rare form of diabetes, a finding that could prove beneficial to those with the more common type 2 diabetes.

In a study published this week in Proceedings of the National Academy of Sciences Early Edition, a team led by Alessandro Doria, M.D., Ph.D. and Rohit N. Kulkarni, M.D., Ph.D., reported that a gene known as BLK is linked to maturity-onset diabetes of the young (MODY), a rare form of diabetes that often strikes before age 25. While types 1 and 2 diabetes are caused by multiple gene variants inherited from both parents, MODY is caused by an autosomal dominant mutation, meaning a person needs to only get the variant from one parent to inherit the disease. While rare, MODY is simpler to diagnose and treat than the other forms of diabetes.

“We have discovered a new function for this gene,” said Doria, Director of the Genetics Core at Joslin Diabetes Center as well as an Associate Professor of Medicine at Harvard Medical School. “We now know it plays a role in increasing insulin production in response to glucose.”

The finding could help in the discovery of new drugs to treat type 2 diabetes, which affects about 24 million Americans and is characterized by high blood-glucose levels that result from the body's inability to increase insulin production in response to increased demands.

“We now have to see how we can take advantage of this discovery,” Doria said. “By studying a rare disorder, we have found something new about insulin secretion that may help us understand more common forms of diabetes.”

Only about two to three percent of those with diabetes have the MODY form. So far, mutations in eight genes have been discovered to cause MODY, but these account for only about 85 percent of the cases of the rare form of the disease. The cause of the remaining 15 percent has been unknown.

“The finding that the mutations affect beta cell function is especially interesting and allows for potential approaches towards developing therapeutics,” said Kulkarni, co-senior author on the paper.

By studying six large MODY families, the researchers traced five mutations to BLK. Normally, BLK triggers insulin production. One of the mutations was found to disrupt BLK’s ability to trigger insulin production. The other four were found to potentially affect BLK expression.

As a result, the authors concluded that BLK plays a previously unsuspected role in the control of insulin synthesis and glucose metabolism.

“We want to study this BLK pathway more to see whether it can be a target for a new drug or other ways to improve beta cell function, especially in people with more common forms of diabetes,” Doria said.

The paper suggests that the gene should be used in genetic tests for autosomal dominant diabetes, particularly in cases where the patients are overweight and the beta cells appear to be functional.

The findings suggest that BLK is a previously unrecognized modulator of the function of beta cells, which make insulin. Diabetes occurs when beta cells in the pancreas fail to secrete insulin appropriately and degenerate.

The paper concludes that the mutations identified in the families studied decrease BLK activity and/or expression, which in turn reduces insulin content and makes beta cells less responsive to glucose, resulting in a reduction in insulin secretion leading to diabetes.

The study was supported by grants from the National Institutes of Health.

Others participating in the research included M. Borowiec, of the Joslin Diabetes Center, the Department of Medicine at Harvard Medical School and the Medical University of Lodz in Poland; C.W. Liew, W. Boonyasrisawat, I. El Khattabi, S.H. Kim, L. Marselli, A.S. Krolewski, Susan Bonner-Weir, A. Sharma and R.N. Kulkarni, all of the Joslin Diabetes Center and the Department of Medicine at Harvard Medical School; R. Thompson and J. Hu of the Joslin Diabetes Center; W.M. Mlynarski of the Medical University of Lodz in Poland; and S.S. Rich, M. Sale and J.C. Mychaleckyj, all of the Center for Public Health Genomics, University of Virginia, Charlottesville.

www.joslin.org