%0 Journal Article
%T Neuroectoderm phenotypes in a human stem cell model of O-GlcNAc transferase associated with intellectual disability.
%A Murray M
%A Davidson L
%A Ferenbach AT
%A Lefeber D
%A van Aalten DMF
%J Mol Genet Metab
%V 142
%N 2
%D 2024 Jun 8
%M 38759397
%F 4.204
%R 10.1016/j.ymgme.2024.108492
%X Pathogenic variants in the O-GlcNAc transferase gene (OGT) have been associated with a congenital disorder of glycosylation (OGT-CDG), presenting with intellectual disability which may be of neuroectodermal origin. To test the hypothesis that pathology is linked to defects in differentiation during early embryogenesis, we developed an OGT-CDG induced pluripotent stem cell line together with isogenic control generated by CRISPR/Cas9 gene-editing. Although the OGT-CDG variant leads to a significant decrease in OGT and O-GlcNAcase protein levels, there were no changes in differentiation potential or stemness. However, differentiation into ectoderm resulted in significant differences in O-GlcNAc homeostasis. Further differentiation to neuronal stem cells revealed differences in morphology between patient and control lines, accompanied by disruption of the O-GlcNAc pathway. This suggests a critical role for O-GlcNAcylation in early neuroectoderm architecture, with robust compensatory mechanisms in the earliest stages of stem cell differentiation.