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

Abstract

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...

Autoantibodies to ICA12 (SOX-13) are not specific for Type I diabetes

“…The frequencies were only slightly increased compared with healthy control subjects indicating that SOX-13 might not represent a major target antigen in autoimmune diabetes. Our data are in contrast to a study reporting on ICA12/SOX-13Ab in 18 % of patients with Type I diabetes and 4.6 % of healthy control subjects [5]. This discrepancy could be partly explained by differences in the composition of subjects studied (long-term vs newly diagnosed diabetes) and differences in the assays.…”

“…The recent description of SOX-13 as the target of ICA12 antibodies made it a promising candidate as a new specific autoantigen to improve the diagnosis of Type I diabetes [5]. In our study we observed a low prevalence of SOX-13Ab in patients with newly diagnosed Type I diabetes (8.8 %), LADA patients (7.0 %) as well as in diabetic patients with single ICA (5.2 %).…”

“…We here used full-length SOX-13 (aa 1±622) instead of truncated proteins (aa 66±604 or a 115±604). It is important to note that the aa sequence described in the earlier study [5] missed the first 18 N-terminal residues deducted from the author's own cDNA clone (AF116 571) and another Genbank report (NM_005 686) [5]. Thus, the SOX-13 protein from that study corresponds to aa 84±622 and aa 133±622 of our full-length clone.…”

“…It is a member of group D SOX-proteins [6] and is ubiquitously expressed in human tissues with highest expressions in pancreas, placenta and kidney [5]. Because autoantibodies against proteins associated with DNA replication and transcription are well known to be present in patients with rheumatic diseases [7], we decided that sera from those patients could serve as optimal controls to determine the specificity of SOX-13Ab.…”

“…Up to now there is only one report on SOX-13 autoantibodies (SOX-13Ab) in patients with Type I diabetes suggesting that ICA12/SOX-13 is a new diabetes-specific autoantigen in Type I diabetes [5].…”