Zscan4 as a candidate conveyor of early developmental defects in O-GlcNAc transferase intellectual disability

Variants in the human β-N-acetylglucosamine (O-GlcNAc) transferase (OGT) gene give rise to an intellectual disability (ID) syndrome termed OGT congenital disorder of glycosylation (OGT-CDG). The mechanisms by which loss of OGT and/or protein O-GlcNAcylation lead to this syndrome are not understood, but symptoms associated with the syndrome suggest a developmental origin. Here, we establish and characterise two lines of mouse embryonic stem cells carrying different patient mutations and show that these mutations lead to disrupted O-GlcNAc homeostasis. Using quantitative proteomics on these cells in the pluripotent state, we identify candidate proteins/pathways that could underpin this syndrome. In addition to the increased levels of OGT and decreased levels of OGA reflecting disrupted O-GlcNAc homeostasis, we find that expression of the ID gene Zscan4 is upregulated. This is associated with increased levels of the OGT:Ten Eleven (Tet) - protein complex that regulates DNA methylation and Zscan4 expression. These data uncover a potential mechanism contributing to the developmental aspects of OGT-CDG.