title: Identification of a SIRT1 mutation in a family with type 1 diabetes.
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.
authors.affiliation: Department of Medicine, University of Fribourg, CH-1700 Fribourg, Switzerland.
authors.forename: Anna
authors.initials: A
authors.lastname: Biason-Lauber
authors.affiliation: Endocrinology, Diabetes, and Metabolism, and Department of Biomedicine, University Hospital Basel, 4031 Basel, Switzerland.
authors.forename: Marianne
authors.initials: M
authors.lastname: Böni-Schnetzler
authors.affiliation: Department of Genetics, Paul F. Glenn Laboratories for the Biological Mechanisms of Aging, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Basil P
authors.initials: BP
authors.lastname: Hubbard
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva, University Medical Center, 1211 Geneva, Switzerland.
authors.forename: Karim
authors.initials: K
authors.lastname: Bouzakri
authors.affiliation: Endocrinology, Diabetes, and Metabolism, and Department of Biomedicine, University Hospital Basel, 4031 Basel, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Brunner
authors.affiliation: Endocrinology, Diabetes, and Metabolism, and Department of Biomedicine, University Hospital Basel, 4031 Basel, Switzerland.
authors.forename: Claudia
authors.initials: C
authors.lastname: Cavelti-Weder
authors.affiliation: Endocrinology, Diabetes, and Metabolism, and Department of Biomedicine, University Hospital Basel, 4031 Basel, Switzerland.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Keller
authors.affiliation: Department of Medicine, University of Fribourg, CH-1700 Fribourg, Switzerland.
authors.forename: Monika
authors.initials: M
authors.lastname: Meyer-Böni
authors.affiliation: Endocrinology, Diabetes, and Metabolism, and Department of Biomedicine, University Hospital Basel, 4031 Basel, Switzerland.
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Meier
authors.affiliation: Glostrup Research Institute, Glostrup University Hospital, 2600 Glostrup, Denmark.
authors.forename: Caroline
authors.initials: C
authors.lastname: Brorsson
authors.affiliation: Endocrinology, Diabetes, and Metabolism, and Department of Biomedicine, University Hospital Basel, 4031 Basel, Switzerland.
authors.forename: Katharina
authors.initials: K
authors.lastname: Timper
authors.affiliation: Endocrinology and Metabolism Service, Department of Medicine, Hadassah Hebrew University Medical Center, 91120 Jerusalem, Israel.
authors.forename: Gil
authors.initials: G
authors.lastname: Leibowitz
authors.affiliation: Functional Genomic Center Zurich, Federal Institute of Technology University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Andrea
authors.initials: A
authors.lastname: Patrignani
authors.affiliation: Functional Genomic Center Zurich, Federal Institute of Technology University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Remy
authors.initials: R
authors.lastname: Bruggmann
authors.affiliation: University of Ottawa, Ottawa, ON K1H 8L6, Canada.
authors.forename: Gino
authors.initials: G
authors.lastname: Boily
authors.affiliation: Endocrinology, Diabetes, and Metabolism, and Department of Biomedicine, University Hospital Basel, 4031 Basel, Switzerland.
authors.forename: Henryk
authors.initials: H
authors.lastname: Zulewski
authors.affiliation: Gastroenterology and Hepatology Center of Integrative Human Physiology and University Hospital Zurich, 8091 Zurich, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Geier
authors.affiliation: Sirtris, a GSK company, Cambridge, MA 02139, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Cermak
authors.affiliation: Sirtris, a GSK company, Cambridge, MA 02139, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Elliott
authors.affiliation: Sirtris, a GSK company, Cambridge, MA 02139, USA.
authors.forename: James L
authors.initials: JL
authors.lastname: Ellis
authors.affiliation: Sirtris, a GSK company, Cambridge, MA 02139, USA.
authors.forename: Christoph
authors.initials: C
authors.lastname: Westphal
authors.affiliation: Endocrinology, Diabetes, and Metabolism, and Department of Biomedicine, University Hospital Basel, 4031 Basel, Switzerland.
authors.forename: Urs
authors.initials: U
authors.lastname: Knobel
authors.affiliation: Department of Clinical Pharmacology and Toxicology Center of Integrative Human Physiology and University Hospital Zurich, 8091 Zurich, Switzerland.
authors.forename: Jyrki J
authors.initials: JJ
authors.lastname: Eloranta
authors.affiliation: University Lille Nord de France, 59045 Lille, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Kerr-Conte
authors.affiliation: University Lille Nord de France, 59045 Lille, France.
authors.forename: François
authors.initials: F
authors.lastname: Pattou
authors.affiliation: University Children's Hospital, 8032 Zurich, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Konrad
authors.affiliation: Department of Cardiology Center of Integrative Human Physiology and University Hospital Zurich, 8091 Zurich, Switzerland.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Matter
authors.affiliation: Institute of Experimental Immunology University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Adriano
authors.initials: A
authors.lastname: Fontana
authors.affiliation: Gastroenterology and Hepatology Center of Integrative Human Physiology and University Hospital Zurich, 8091 Zurich, Switzerland.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Rogler
authors.affiliation: Functional Genomic Center Zurich, Federal Institute of Technology University of Zurich, 8057 Zurich, Switzerland.
authors.forename: Ralph
authors.initials: R
authors.lastname: Schlapbach
authors.affiliation: Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
authors.forename: Camille
authors.initials: C
authors.lastname: Regairaz
authors.affiliation: Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
authors.forename: José M
authors.initials: JM
authors.lastname: Carballido
authors.affiliation: Endocrinology and Metabolism Service, Department of Medicine, Hadassah Hebrew University Medical Center, 91120 Jerusalem, Israel.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Glaser
authors.affiliation: University of Ottawa, Ottawa, ON K1H 8L6, Canada.
authors.forename: Michael W
authors.initials: MW
authors.lastname: McBurney
authors.affiliation: Glostrup Research Institute, Glostrup University Hospital, 2600 Glostrup, Denmark.
authors.forename: Flemming
authors.initials: F
authors.lastname: Pociot
authors.affiliation: Department of Genetics, Paul F. Glenn Laboratories for the Biological Mechanisms of Aging, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Sinclair
authors.affiliation: Endocrinology, Diabetes, and Metabolism, and Department of Biomedicine, University Hospital Basel, 4031 Basel, Switzerland.
authors.forename: Marc Y
authors.initials: MY
authors.lastname: Donath
mesh_terms: D000704:Analysis of Variance; D015551:Autoimmunity / Q000235:genetics*; D001483:Base Sequence; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D008969:Molecular Sequence Data; D016296:Mutagenesis; D020125:Mutation, Missense / Q000235:genetics; D009569:Nitric Oxide / Q000378:metabolism; D010375:Pedigree; D060888:Real-Time Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D056564:Sirtuin 1 / Q000235:genetics*; D013557:Switzerland
chemical_list: D018925:Chemokines; D016207:Cytokines; D009569:Nitric Oxide; C447939:SIRT1 protein, human; D056564:Sirtuin 1