Faculté des sciences

Identification of a SIRT1 Mutation in a Family with Type 1 Diabetes

Biason-Lauber, Anna ; Böni-Schnetzler, Marianne ; Hubbard, Basil P. ; Bouzakri, Karim ; Brunner, Andrea ; Cavelti-Weder, Claudia ; Keller, Cornelia ; Meyer-Böni, Monika ; Meier, Daniel T. ; Brorsson, Caroline ; Timper, Katharina ; Leibowitz, Gil ; Patrignani, Andrea ; Bruggmann, Remy ; Boily, Gino ; Zulewski, Henryk ; Geier, Andreas ; Cermak, Jennifer M. ; Elliott, Peter ; Ellis, James L. ; Westphal, Christoph ; Knobel, Urs ; Eloranta, Jyrki J. ; Kerr-Conte, Julie ; Pattou, François ; Konrad, Daniel ; Matter, Christian M. ; Fontana, Adriano ; Rogler, Gerhard ; Schlapbach, Ralph ; Regairaz, Camille ; Carballido, José M. ; Glaser, Benjamin ; McBurney, Michael W. ; Pociot, Flemming ; Sinclair, David A. ; Donath, Marc Y.

In: Cell Metabolism, 2013, vol. 17, no. 3, p. 448-455

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... Plus

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    Summary
    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