Alternative splicing of G6PC2, the gene coding for the islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP), results in differential expression in human thymus and spleen compared with pancreas

Autoimmunity to insulin, glutamic acid decarboxylase and the tyrosine-phosphatase-like protein IA-2 is associated with type 1 diabetes. The production of self-molecules in thymus and secondary lymphoid tissues is critical for self-tolerance; reduced levels may impair tolerance and predispose to autoimmunity, as shown for insulin. Alternative splicing causes differential expression of IA-2 gene (PTPRN) transcripts and IA-2 protein in human thymus and spleen compared with pancreas. IA-2 sequences not present in lymphoid tissues become autoimmune targets in type 1 diabetes. The beta cell molecule islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) is an autoantigen in the non-obese diabetic (NOD) mouse, a model of type 1 diabetes. IGRP is a candidate autoantigen in the human disease, but robust assays for IGRP autoantibodies and/or autoreactive T cells are not available. Both full-length and IGRP splice variants encoded by the G6PC2 gene are expressed in the pancreas. In this study we tested the hypothesis that IGRP splice variants could be differentially expressed in thymus and spleen compared with the pancreas. We evaluated the expression of G6PC2 transcripts in matched human thymus, spleen and pancreas specimens by RT-PCR. Alternative splicing results in differential expression of G6PC2 transcripts in thymus and spleen compared with pancreas. The full-length transcript is expressed in human pancreas but not in thymus or spleen. Five alternative spliced forms are always expressed in pancreas but those lacking exons 2, 3 and 4, alone or in combination, were rarely detected in thymus or spleen. Conclusions/interpretation: Differential tissue expression might favour autoimmune responses to IGRP in humans; target epitopes may be encoded by exons 3 and 4, or at the junctions of the conserved exons in the spliced transcripts. This information may aid in designing synthetic peptides for the identification of IGRP-specific autoreactive T cells in patients with type 1 diabetes.