Public Release: 

Gene Mutation Associated With Rare Form Of Diabetes

Massachusetts General Hospital

Researchers at the Massachusetts General Hospital (MGH) have discovered that a mutation in a gene that plays a critical role in insulin secretion is associated with a rare, inherited form of diabetes. They also suspect that tiny changes in this gene might be involved in more common forms of type 2 (adult-onset) diabetes. Their report appears in the October issue of Nature Genetics.

"We've identified a new type of diabetes that has a clear origin in a single genetic mutation," says Joel Habener, MD, of the MGH Laboratory of Molecular Endocrinology, who led the study. "Learning more about this gene may lead us to greater insights into common forms of diabetes that are associated with a variety of genetic and environmental factors." Habener also is an investigator with the Howard Hughes Medical Institute.

Diabetes is known to run in families, but common forms of the illness are not inherited in a classic Mendelian fashion -- in which the offspring of affected individuals have a predictable risk of inheriting a disease. Therefore scientists believe that several genes, as well as environmental factors, are involved in determining whether or not an individual will develop diabetes.

However, there are rare forms of type 2 diabetes that do follow a Mendelian pattern of inheritance; each child of an affected individual has a 50 percent chance of becoming diabetic -- indicating that inheritance of a single mutated copy of a gene is sufficient to cause illness. In addition, symptoms of these forms of diabetes first appear when individuals are in their 20s or 30s, compared to common type 2 diabetes, in which symptoms appear in the 40s or 50s. As a result, these forms are called maturity-onset diabetes of the young (MODY).

Three separate genes previously have been associated with forms of MODY; the current paper describes a new form, associated with a gene called insulin promoting factor-1 (ipf-1). This gene is known to be critical in the development of the insulin-secreting beta cells and in stimulating those cells to release insulin in response to rising blood-sugar levels.

Swedish researchers studying ipf-1 discovered that mice without a working copy of the gene never develop a pancreas. Such a phenomenon had never been reported in humans until a member of the MGH team, Doris Stoffers, MD, PhD, first author of the current paper, heard about a baby born without a pancreas in a family with a strong history of diabetes. The child had been under the care of William Clarke, MD, of the University of Virginia Medical School -- a collaborator in the current study -- and was successful treated with insulin therapy. In a study published earlier this year, the MGH-based team reported that this child had identical mutations in both copies of the ipf-1 gene, indicating that the same mutation had been inherited from both parents.

For the current study, the MGH team tested many members of the child's large, extended family and compared that information with the appearance of diabetes over six generations. They found that most of those with diabetes had a single copy of the same mutation seen in the child. The mutation also was seen in several younger members of the family -- including the child's mother -- who had not yet developed diabetes but could in the future. The child's father, who also carries the mutation, had developed diabetes at age 17.

While this particular form of diabetes, called MODY4, is rare, the MGH team believes that further study of the ipf-1 gene may yield information key to understanding common type 2 diabetes. "This gene is critical to insulin secretion, and it is likely that other mutations in this gene will be seen in other families with diabetes," says Habener. "This unusual mutation completely inactivates the gene. But tiny changes in the gene, changes in a single amino acid, might result in a gene that works pretty well but is vulnerable to future damage. That vulnerability could be associated with the obesity-associated diabetes that has been exploding in recent years."

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