Researchers find a genetic cause of type 1 diabetes and autoimmunity

December 04, 2000

St. Louis, Dec. 5, 2000--Investigators at Washington University School of Medicine in St. Louis have identified a novel gene that causes an inherited form of type 1, or insulin-dependent, diabetes and autoimmunity. This finding might lead to ways to prevent type 1 diabetes.

The research team, led by Talal A. Chatila, M.D., associate professor of pediatrics, and Anne M. Bowcock, Ph.D., professor of genetics, studied blood samples from two families affected by a rare disorder that affects only boys and causes type 1 diabetes and allergies. They found mutations in a gene located in a region of the X chromosome previously linked to type 1 diabetes.

"This is an example of a single gene defect causing a high incidence of type 1 diabetes in affected children. It provides us with an important tool for dissecting the genetics of type 1 diabetes and deciphering how the disease comes about in the general population," said Chatila, lead author of the study. The results will be published Dec. 15 in the Journal of Clinical Investigation and are posted on JCI's web site at

Many children with the disorder, called X-linked autoimmunity-allergic disregulation syndrome (XLAAD), show the classic signs of diabetes. They also suffer from chronic diarrhea and eczema. Because XLAAD causes severe wasting, it often kills babies during the first months of life.

Mutations in a single gene called JM2 cause the disease, the researchers found. The mutations adversely affect the function of the protein the gene encodes.

Identification of the gene, Chatila said, supports the idea that a limited number of genes are critical for the development of diabetes and other autoimmune disorders. "Now we need to carefully investigate whether the pathway that involves this gene is mutated in other patients with type 1 diabetes and whether other genes collaborate with this gene in the disease," he added.

Between 500,000 to 1 million people in the United States have type 1 diabetes, which usually begins in children or young adults. It develops when immune system cells called T lymphocytes kill islet cells in the pancreas that produce insulin. Insulin "unlocks" the cells of the body, allowing glucose to enter and fuel them. When cells don't obtain enough fuel, they can't function.

The two families in the study had five affected males. All five suffered from type 1 diabetes, chronic diarrhea and severe allergic reactions. Other family members were not affected.

The researchers found mutations in JM2 in all the affected males. This gene codes for a transcription factor--a protein that regulates the activity of other genes.

Chatila's working model is that defects in the JM2 protein make T lymphocytes--the immune cells that mediate type 1 diabetes and abet the allergy--hyperactive and likely to destroy islet cells. "They're easy to activate and difficult to shut down," he said. Understanding how JM2 regulates the immune response and how defects in this protein cause type 1 diabetes will provide important insights into the development of the disease and into ways of preventing its onset, Chatila added.
Chatila TA, Blaeser F, Nga H, Lederman HM, Voulgaropoulos C, Helms C, Bowcock AM. JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome. Journal of Clinical Investigation, Dec. 15, 2000.

Grants from the National Institutes of Health supported this research.

The full-time and volunteer faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC Health Care.

Washington University School of Medicine

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