December 3, 1999

MGH researchers identify gene malfunction in type 1 diabetes

An MGH research study has identified a gene malfunction that appears to be central to the development of type 1 diabetes.

The study in a mouse model of type 1 diabetes found that a gene required to help teach the immune system to recognize so-called "self" proteins is somehow inactivated, even though its sequence is not mutated. The scientists also found that the inactivation of this gene called Lmp2 has a profound impact on another key protein called nuclear factor kappa-B (NF-kB), a major controller of several immune system activities. Finding ways to correct or circumvent the malfunction identified in this study may lead to ways of preventing or stopping the autoimmune reaction at the heart of type 1 diabetes.

"This is a true genetic abnormality we can associate with type 1 diabetes," says Denise Faustman, MD, PhD, of the MGH Diabetes Unit, who led the study appearing in the December issue of Molecular and Cellular Biology. "While Lmp2 is located in a portion of the genome that had been linked to the disease, it hadn't been considered a candidate because its sequence is normal. But studying the gene's function has shown us a previously unsuspected problem: In the immune system cells we looked at, the Lmp2 protein virtually disappears by the time these mice reach a certain age, therefore most likely initiating their diabetes."

Faustman and her postdoctoral fellow Takuma Hayashi, PhD, also found that lack of the Lmp2 protein impairs the activity of a second protein called NF-kB. "Finding the connection with NF-kB was unexpected and quite exciting," Faustman says. "It is one of the most important proteins we know about for controlling major immune system activities, but no one suspected it could be involved in diabetes or other autoimmune diseases. These findings are bringing seemingly unrelated areas of basic research together to address one of the most significant human diseases."