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

Abstract

Aims/hypothesis: Autoimmunity to insulin, glutamic acid decarboxylase and the tyrosine-phosphatase-like protein IA-2 is associated with type 1 diabetes.

Variations in the G6PC2/ABCB11 genomic region are associated with fasting glucose levels

“…The longer cDNA including exon 4 has approximately 50% homology with glucose-6-phosphatase catalytic subunit (G6pc) across a variety of species including humans and is membrane bound in the endoplasmic reticulum (46). The corresponding G6PC2 splice forms have been observed in human pancreas (47). rs560887 is located in intron 3, just 26 bp proximal to exon 4, raising the possibility that this variant may play a role in whether the full-length transcript is formed.…”

Autoreactive T cells in type 1 diabetes

“…Differential expression of IA-2 and IGRP mRNAs in thymus and pancreas (157,158) may promote autoimmunity, as the immune system may not be tolerant to alternatively spliced variants expressed in pancreas but not thymus (159). Many autoantigens in autoimmune disease are post-translationally modified (PTM) (160).…”

Antigen Targets of Type 1 Diabetes Autoimmunity

“…One important example of emerging interest is that epitopes may never be presented in the thymus, simply because they are generated as neoantigens in the periphery as a result of posttranslational modifications (Diez et al 2001;Mannering et al 2005;Dogra et al 2006). From our understanding of the pathogenesis of other autoimmune and inflammatory diseases it has become clear that proteins can be altered from their germline encoding sequence (which is thymically expressed) by a variety of cell biological modifications, and as a result give rise to new antigens against which tolerance does not exist.…”