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Cell Metab. 2013 Mar 5;17(3):448-455. doi: 10.1016/j.cmet.2013.02.001.

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

Author information

1
Department of Medicine, University of Fribourg, CH-1700 Fribourg, Switzerland.
2
Endocrinology, Diabetes, and Metabolism, and Department of Biomedicine, University Hospital Basel, 4031 Basel, Switzerland.
3
Department of Genetics, Paul F. Glenn Laboratories for the Biological Mechanisms of Aging, Harvard Medical School, Boston, MA 02115, USA.
4
Department of Genetic Medicine and Development, University of Geneva, University Medical Center, 1211 Geneva, Switzerland.
5
Glostrup Research Institute, Glostrup University Hospital, 2600 Glostrup, Denmark.
6
Endocrinology and Metabolism Service, Department of Medicine, Hadassah Hebrew University Medical Center, 91120 Jerusalem, Israel.
7
Functional Genomic Center Zurich, Federal Institute of Technology University of Zurich, 8057 Zurich, Switzerland.
8
University of Ottawa, Ottawa, ON K1H 8L6, Canada.
9
Gastroenterology and Hepatology Center of Integrative Human Physiology and University Hospital Zurich, 8091 Zurich, Switzerland.
10
Sirtris, a GSK company, Cambridge, MA 02139, USA.
11
Department of Clinical Pharmacology and Toxicology Center of Integrative Human Physiology and University Hospital Zurich, 8091 Zurich, Switzerland.
12
University Lille Nord de France, 59045 Lille, France.
13
University Children's Hospital, 8032 Zurich, Switzerland.
14
Department of Cardiology Center of Integrative Human Physiology and University Hospital Zurich, 8091 Zurich, Switzerland.
15
Institute of Experimental Immunology University of Zurich, 8057 Zurich, Switzerland.
16
Novartis Institutes for BioMedical Research, 4002 Basel, Switzerland.
#
Contributed equally

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.

PMID:
23473037
PMCID:
PMC3746172
DOI:
10.1016/j.cmet.2013.02.001
[Indexed for MEDLINE]
Free PMC Article
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