Sex-determining region Y-related protein SOX13 is a diabetes autoantigen expressed in pancreatic islets

The SOX (sex-determining region [SRY]-type high mobility group [HMG] box) f amily of transcription factors play key roles in determining cell fate duri ng organ development. In this study, we have identified a new human SOX gen e, SOX13, as encoding the type 1 diabetes autoantigen, islet cell antigen 1 2 (ICA12). Sequence analysis showed that SOX13 belongs to the class D subgr oup of SOX transcription factors, which contain a leucine zipper motif and a region rich in glutamine. SOX13 autoantibodies occurred at a significantl y higher frequency among 188 people with type 1 diabetes (18%) than among 8 8 with type 2 diabetes (6%) or 175 healthy control subjects (4%). Deletion mapping of the antibody epitopes showed that the autoantibodies mere primar ily directed against an epitope requiring the majority of the protein. SOX1 3 RNA was detected in most human tissues, with the highest levels in the pa ncreas, placenta, and kidney. Immunohistochemistry on sections of human pan creas identified SOX13 in the islets of Langerhans, where staining was most ly cytoplasmic. In mouse pancreas, Sox13 was present in the nucleus and cyt oplasm of beta-cells as well as other islet cell types. Recombinant SOX13 p rotein bound to the SOX consensus DNA motif AACAAT, and binding was inhibit ed by homodimer formation. These observations-along with the known molecula r interactions of the closely related protein, rainbow trout Sox23-suggest that SOX13 may be activated for nuclear import and DNA binding through hete rodimer formation. In conclusion, we have identified ICA12 as the putative transcription factor SOX13 and demonstrated an increased frequency of autoa ntibody reactivity in sera from type 1 diabetic subjects compared with type 2 diabetic and healthy control subjects.