Biason-Lauber, Anna1; Böni-Schnetzler, Marianne1; Hubbard, Basil P1; Bouzakri, Karim1; Brunner, Andrea1; Cavelti-Weder, Claudia1; Keller, Cornelia1; Meyer-Böni, Monika1; Meier, Daniel T1; Brorsson, Caroline2; Timper, Katharina1; Leibowitz, Gil1; Patrignani, Andrea1; Bruggmann, Remy1; Boily, Gino1; Zulewski, Henryk1; Geier, Andreas1; Cermak, Jennifer M1; Elliott, Peter1; Ellis, James L1; Westphal, Christoph1; Knobel, Urs1; Eloranta, Jyrki J1; Kerr-Conte, Julie1; Pattou, François1; Konrad, Daniel1; Matter, Christian M1; Fontana, Adriano1; Rogler, Gerhard1; Schlapbach, Ralph1; Regairaz, Camille1; Carballido, José M1; Glaser, Benjamin1; McBurney, Michael W1; Pociot, Flemming2; Sinclair, David A1; Donath, Marc Y1
1 unknown2 Paediatrics, Herlev and Gentofte Hospital, The Capital Region of Denmark
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.