1. Identification of a SIRT1 mutation in a family with type 1 diabetes.
- Author
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Biason-Lauber A, Böni-Schnetzler M, Hubbard BP, Bouzakri K, Brunner A, Cavelti-Weder C, Keller C, Meyer-Böni M, Meier DT, Brorsson C, Timper K, Leibowitz G, Patrignani A, Bruggmann R, Boily G, Zulewski H, Geier A, Cermak JM, Elliott P, Ellis JL, Westphal C, Knobel U, Eloranta JJ, Kerr-Conte J, Pattou F, Konrad D, Matter CM, Fontana A, Rogler G, Schlapbach R, Regairaz C, Carballido JM, Glaser B, McBurney MW, Pociot F, Sinclair DA, and Donath MY
- Subjects
- Analysis of Variance, Base Sequence, Chemokines metabolism, Cytokines metabolism, Humans, Immunoprecipitation, Male, Molecular Sequence Data, Mutagenesis, Mutation, Missense genetics, Nitric Oxide metabolism, Pedigree, Real-Time Polymerase Chain Reaction, Sequence Analysis, DNA, Switzerland, Autoimmunity genetics, Diabetes Mellitus, Type 1 genetics, Genetic Predisposition to Disease genetics, Sirtuin 1 genetics
- Abstract
Type 1 diabetes is caused by autoimmune-mediated β cell destruction leading to insulin deficiency. The histone deacetylase SIRT1 plays an essential role in modulating several age-related diseases. Here we describe a family carrying a mutation in the SIRT1 gene, in which all five affected members developed an autoimmune disorder: four developed type 1 diabetes, and one developed ulcerative colitis. Initially, a 26-year-old man was diagnosed with the typical features of type 1 diabetes, including lean body mass, autoantibodies, T cell reactivity to β cell antigens, and a rapid dependence on insulin. Direct and exome sequencing identified the presence of 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. These observations identify a role for SIRT1 in human autoimmunity and unveil a monogenic form of type 1 diabetes., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
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