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.
Bibliographical noteFunding Information:
We thank the patients and families whose participation made this study possible. This work was supported by grants from the Juvenile Diabetes Research Foundation, the Swiss National Science Foundation, the Zürich Centre for Integrated Human Physiology, the Glenn Foundation for Medical Research, and the Ellison Medical Foundation; by NIA/NIH grants; by an unrestricted grant from Sirtris, a GSK company; and by an NSERC PGS-D Fellowship (to B.P.H.). A.F. is Hertie Senior Research Professor Neuroscience 2009 of the Gemeinnützige Hertie-Stiftung. This research utilizes resources provided by the Type 1 Diabetes Genetics Consortium, a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, the National Human Genome Research Institute, the National Institute of Child Health and Human Development, and the Juvenile Diabetes Research Foundation and supported by U01 DK062418.