An <i>O</i>-GlcNAc transferase pathogenic variant linked to intellectual disability affects pluripotent stem cell self-renewal
Michaela Omelková, Christina Fenger, Marta Murray, Trine Bjørg Hammer, Veronica M. Pravatà, Sergio G. Bartual, Ignacy Czajewski, Allan Bayat, Andrew T. Ferenbach, Marios P. Stavridis, Daan M. F. van Aalten
Abstract
O-linked β-N-acetylglucosamine (O-GlcNAc) transferase (OGT) is an essential enzyme that modifies proteins with O-GlcNAc. Inborn OGT genetic variants were recently shown to mediate a novel type of congenital disorder of glycosylation (OGT-CDG), which is characterised by X-linked intellectual disability (XLID) and developmental delay. Here, we report an OGTC921Y variant that co-segregates with XLID and epileptic seizures, and results in loss of catalytic activity. Colonies formed by mouse embryonic stem cells carrying OGTC921Y showed decreased levels of protein O-GlcNAcylation accompanied by decreased levels of Oct4 (encoded by Pou5f1), Sox2 and extracellular alkaline phosphatase (ALP), implying reduced self-renewal capacity. These data establish a link between OGT-CDG and embryonic stem cell self-renewal, providing a foundation for examining the developmental aetiology of this syndrome.