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

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• 作者：Anna Biason-Lauber¹ ; ¹⁷ ; Marianne Bö ; ni-Schnetzler² ; ¹⁷ ; Basil P. Hubbard³ ; ¹⁷ ; Karim Bouzakri⁴ ; ¹⁷ ; Andrea Brunner² ; Claudia Cavelti-Weder² ; Cornelia Keller² ; Monika Meyer-Bö ; ni¹ ; Daniel T. Meier² ; Caroline Brorsson⁵ ; Katharina Timper² ; Gil Leibowitz⁶ ; Andrea Patrignani⁷ ; Remy Bruggmann⁷ ; Gino Boily⁹ ; Henryk Zulewski² ; Andreas Geier¹⁰ ; Jennifer M. Cermak¹³ ; Peter Elliott¹³ ; James L. Ellis¹³ ; Christoph Westphal¹³ ; Urs Knobel² ; Jyrki J. Eloranta¹¹ ; Julie Kerr-Conte¹⁴ ; Franç ; ois Pattou¹⁴ ; Daniel Konrad¹⁵ ; Christian M. Matter¹² ; Adriano Fontana⁸ ; Gerhard Rogler¹⁰ ; Ralph Schlapbach⁷ ; Camille Regairaz¹⁶ ; José ; M. Carballido¹⁶ ; Benjamin Glaser⁶ ; Michael W. McBurney⁹ ; Flemming Pociot⁵ ; David A. Sinclair³ ; Marc Y. Donath² ; ^{marc.donath@usb.ch}
• 刊名：Cell Metabolism
• 出版年：2013
• 出版时间：5 March, 2013
• 年：2013
• 卷：17
• 期：3
• 页码：448-455
• 全文大小：957 K

文摘

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Summary

Type 1 diabetes is caused by autoimmune-mediated ¦Â 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?¦Â 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.