How genetic mutations lead to diabetes

Scientists at The Scripps Research Institute have finally cracked the 40-year-old mystery of how certain genetic mutations lead to Type 1 diabetes.

According to researchers, their findings could lead to novel therapies for Type 1 diabetes and other autoimmune diseases.

"People have been looking for the mechanism linking HLA and autoimmunity for 40 years. This study provides a big leap forward in understanding and suggests a critical new target to intervene in type 1 diabetes," said Scripps Research Professor Luc Teyton, who led the study with Scripps Research Professor Ian Wilson.

While genes predispose people to many different types of diseases in many different ways, specific genetic variations are especially strong predictor of the development of type 1 diabetes.

Three genetic variations in particular (HLA-DQ2, HLA-DQ8, and HLA-DR0405)-all located in the region of the genome called HLA for "human leukocyte antigen"-are known to dramatically increase risk of coming down with the condition.

These three genes encode molecules that present peptides (protein fragments) to the body's T cells. T cells then determine whether the peptide being presented is dangerous and needs to be eliminated from the body-as in the case of foreign invaders such as bacteria or viruses-or whether the peptide is "self," part of the host and something the immune system needs to leave alone. However, in the context of type 1 diabetes, T cells aggressively attack the body's own cells.

The scientists wanted to know on a molecular level how mutations in the immune surveillance machinery could lead to type 1 diabetes.

Research Associate Adam Corper of the Wilson lab, who was first author of the paper with Kenji Yoshida of the Teyton lab, said: "We were interested in trying to understand why certain MHC molecules (which are molecules in mice analogous to HLA molecules in humans) are linked to autoimmune disease, particularly type 1 diabetes. In particular, we wanted to know why a single residue at position 57 on the ß chain of HLA molecules seems to be linked to the disease."

In the new research, the team used a series of structural and biophysical studies to answer that question.

The study was published in an advanced, online issue of the Journal of Clinical Investigation on April 19, 2010, and will appear in the May print edition of the journal.