The SOX (sex-determining region [SRY]-type high mobility group [HMG] box) family of transcription factors play key roles in determining cell fate during organ development. In this study, we have identified a new human SOX gene, S O X 1 3, as encoding the type 1 diabetes autoantigen, islet cell antigen 12 (ICA12). Sequence analysis showed that SOX13 belongs to the class D subgroup of SOX transcription factors, which contain a leucine zipper motif and a region rich in glutamine. SOX13 autoantibodies occurred at a significantly higher frequency among 188 people with type 1 diabetes (18%) than among 88 with type 2 diabetes (6%) or 175 healthy control subjects (4%). Deletion mapping of the antibody epitopes showed that the autoantibodies were primarily directed against an epitope requiring the majority of the protein. S O X 1 3 R N A was detected in most human tissues, with the highest levels in the pancreas, placenta, and kidney. Immunohistochemistry on sections of human pancreas identified SOX13 in the islets of Langerhans, where staining was mostly cytoplasmic. In mouse pancreas, Sox13 was present in the nucleus and cytoplasm of -cells as well as other islet cell types. Recombinant SOX13 protein bound to the SOX consensus DNA motif AACAAT, and binding was inhibited by homodimer formation. These observations-along with the known molecular interactions of the closely related protein, rainbow trout Sox23-suggest that SOX13 may be activated for nuclear import and DNA binding through heterodimer formation. In conclusion, we have identified ICA12 as the putative transcription factor SOX13 and demonstrated an increased frequency of autoantibody reactivity in sera from type 1 diabetic subjects compared with type 2 diabetic and healthy control subjects. T ype 1 diabetes results from the destruction of pancreatic islet -cells by an autoimmune response to -cell constituents, which is initiated by an unknown environmental agent acting on a susceptible genetic background. Identification of GAD (1), a family of tyrosine phosphatase-like proteins variously designated islet cell antigen 512 (ICA512)/IA-2/IA-2 (2,3), and insulin (4) as autoantigens in type 1 diabetes has led to the proposal of several mechanisms for the initiation and progression of islet autoimmunity. These include molecular mimicry between GAD and coxsackievirus B (5) or between ICA512 and rotavirus (6), hyperexpression of GAD in response to metabolic stress (7), and lack of tolerance to (pro)insulin as a consequence of genetic variation of proinsulin expression levels in the thymus (8,9). The multifactorial nature of type 1 diabetes and the association of numerous environmental agents with the disease (10) suggest that there may be multiple pathways leading to -cell autoimm u n i t y. To attain a better understanding of the pathogenesis of type 1 diabetes, the autoimmune response to islet -c e l l s needs to be fully characterized.In a search for novel diabetes-associated autoantigens, the screen of an islet cDNA expression library with type 1 diabetes sera tha...
SOX13 is an islet cell autoantigen (ICA12), identified by antibody screening of an islet cDNA library, using sera from patients with Type 1 diabetes. We ascertained the frequency of antibody reactivity to SOX13 and compared it with other Type 1 diabetes autoantibody reactivities. Antibodies were measured by radioimmunoprecipitation (RIP) using (35) S labelled SOX13 expressed in rabbit reticulocyte lysate. Sera from 109 subjects with Type 1 diabetes, 29 with Type 2 diabetes, 144 with other autoimmune diseases and from 201 controls were tested for anti-SOX13, and results were compared with the frequency of antibodies to glutamic acid decarboxylase (anti-GAD), islet cell antigen 512 (anti-ICA512) and islet cell cytoplasm (ICA). Anti-SOX13 were detected in 20 (18.3%) of 109 subjects with Type 1 diabetes, and more frequently in adults than in children (29% vs 10%). Anti-SOX13 usually occurred with anti-GAD but rarely with anti-ICA512. Seven sera positive for anti-SOX13 did not react with either GAD, ICA512 or islet cell cytoplasm indicating that anti-SOX13 represented a distinct population of antibodies. Reactivity to SOX13 represents a further autoantibody response in adults with Type 1 diabetes and may provide a useful disease marker in subjects in whom other autoantibody tests are negative.
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