First single gene mutation shown to result in type 1 diabetes

The research began when Marc Donath, M.D., endocrinologist and researcher at the University Hospital Basel in Switzerland, discovered an interesting pattern of autoimmune disease within the family of one of his patients, a 26-year-old male who had recently been diagnosed with T1D. The patient showed an uncommonly strong family history of T1D; his sister, father, and paternal cousin had also been diagnosed earlier in their lives. Additionally, another family member had developed ulcerative colitis, also an autoimmune disease.

"This pattern of inheritance was indicative of dominant genetic mutation, and we therefore decided to attempt to identify it," Dr. Donath said.

Four years of analysis using three different genotyping and sequencing techniques pointed to a mutation on the SIRT1 gene as the common indicator of autoimmune disease within the family. The SIRT1 gene plays a role in regulating metabolism and protecting against age-related disease. To gain more understanding of how this genetic change in SIRT1 leads to T1D, Dr. Donath and his team performed additional studies with animal models of T1D. When the mutant SIRT1 gene found in the families was expressed in beta cells, those beta cells generated more mediators that were destructive to them. Furthermore, knocking out the normal SIRT1 gene in mice resulted in their becoming more susceptible to diabetes with greatly increased islet destruction. Dr. Donath speculates that the beta cell impairment and death due to the SIRT1 mutation subsequently activates the immune system toward T1D.

"The identification of a gene leading to type 1 diabetes could allow us to understand the mechanism responsible for the disease and may open up new treatment options," Dr. Donath explained.

Patricia Kilian, Ph.D., director of the Beta Cell Regeneration Program at JDRF, concurred, and said that the development is exciting for many reasons: "While the change in the genetic makeup within this family with type 1 diabetes is rare, the discovery of the role of the SIRT1 pathway in affecting beta cells could help scientists find ways to enhance beta cell survival and function in more common forms of the disease. This study also reinforces increasing evidence that abnormal beta cell function has a role in the development of type 1 diabetes, and that blocking or reversing early stages of beta cell dysfunction may help prevent or significantly delay the disease's onset. Drug companies are already in the process of developing SIRT1 activators, which could eventually speed our ability to translate these new research findings into meaningful therapies for patients."

JDRF is continuing to fund research by Dr. Donath that builds off of these latest findings.