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Identification of a SIRT1 mutation in a family with Type 1 Diabetes

Biason-Lauber, Anna and Böni-Schnetzler, Marianne and Hubbard, Basil P and Bouzakri, Karim and Brunner, Andrea and Cavelti-Weder, Claudia and Keller, Cornelia and Meyer-Böni, Monika and Meier, Daniel T and Brorsson, Caroline and Timper, Katharina and Leibowitz, Gil and Patrignani, Andrea and Bruggmann, Remy and Boily, Gino and Zulewski, Henryk and Geier, Andreas and Cermak, Jennifer M and Elliott, Peter and Ellis, James L and Westphal, Christoph and Knobel, Urs and Eloranta, Jyrki J and Kerr-Conte, Julie and Pattou, François and Konrad, Daniel and Matter, Christian M and Fontana, Adriano and Rogler, Gerhard and Schlapbach, Ralph and Regairaz, Camille and Carballido, Jose and Glaser, Benjamin and McBurney, Michael W and Pociot, Flemming and Sinclair, David A and Donath, Marc Y (2012) Identification of a SIRT1 mutation in a family with Type 1 Diabetes. Cell Metabolism, 17 (3). pp. 448-455. ISSN 1550-4131

Abstract

Type 1 diabetes is caused by autoimmune-mediated
b 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 b 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.§

Item Type: Article
Keywords: Type 1 diabetes, genetics, Sirtuin-1, metabolism
Date Deposited: 13 Oct 2015 13:15
Last Modified: 13 Oct 2015 13:15
URI: https://oak.novartis.com/id/eprint/5451

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