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Mar 6, 2013

Single Gene Mutation May Cause Type 1 Diabetes

  • A single gene, SIRT1, may be involved in the development of type 1 diabetes (T1D) and other autoimmune diseases, according to researchers at University Hospital Basel in Switzerland. The team says that the finding represents the first demonstration of a monogenetic defect leading to the onset of T1D.

    One of the researchers, Marc Donath, M.D., noticed a 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 says.

    The team spent four years analyzing data using three different genotyping and sequencing techniques. Their investigation 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. Analysis showed that the family’s mutation exhibited a T-to-C exchange in exon 1 of SIRT1, corresponding to a leucine-to-proline mutation at residue 107. Expression of SIRT1-L107P in insulin-producing cells resulted in overproduction of nitric oxide, cytokines, and chemokines.

    Dr. Donath and his team performed additional studies with animal models of type 1 diabetes. T1D is caused by autoimmune-mediated beta cell destruction leading to insulin deficiency. When the mutant SIRT1 gene found in the families was expressed in beta cells in the animals, 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 explains.

    “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,” added Patricia Kilian, Ph.D., director of the Beta Cell Regeneration Program at JDRF. “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.”

    The study was published yesterday in Cell Metabolism and was funded by JDRF. The paper is titled “Identification of a SIRT1 Mutation in a Family with Type 1 Diabetes”.


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