Identification of a SIRT1 mutation in a family with type 1 diabetes.
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.
T10 T11 T12 T13 T14 T15 T16 T17 T1 T2 T3 T4 T5 T6 T7 T8 T9
GENE-Y GENE-N GENE-Y GENE-Y GENE-N GENE-N GENE-Y GENE-Y CHEMICAL CHEMICAL CHEMICAL GENE-N GENE-Y GENE-Y GENE-Y GENE-Y GENE-N
SIRT1 L107P insulin insulin cytokines chemokines SIRT1 SIRT1 leucine proline nitric oxide histone deacetylase SIRT1 SIRT1 insulin SIRT1 leucine-to-proline mutation at residue 107