期刊
CELL METABOLISM
卷 17, 期 3, 页码 448-455出版社
CELL PRESS
DOI: 10.1016/j.cmet.2013.02.001
关键词
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资金
- Juvenile Diabetes Research Foundation
- Swiss National Science Foundation
- Zurich Centre for Integrated Human Physiology
- Glenn Foundation for Medical Research
- Ellison Medical Foundation
- NIA/NIH
- Sirtris, a GSK company
- NSERC PGS-D Fellowship
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Institute of Allergy and Infectious Diseases
- National Human Genome Research Institute
- National Institute of Child Health and Human Development
- [U01 DK062418]
Type 1 diabetes is caused by autoimmune-mediated beta 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 beta 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.
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