Identification of a SIRT1 mutation in a family with type 1 diabetes

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

    100 Citationer (Scopus)

    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.
    OriginalsprogEngelsk
    TidsskriftCell Metabolism
    Vol/bind17
    Udgave nummer3
    Sider (fra-til)448-55
    Antal sider8
    ISSN1550-4131
    DOI
    StatusUdgivet - 5 mar. 2013

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