Neuroectoderm phenotypes in a human stem cell model of O-GlcNAc transferase associated with intellectual disability

Marta Murray, Lindsay Davidson, Andrew T. Ferenbach, Dirk Lefeber, Daan M.F. van Aalten*

*Corresponding author for this work

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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.

Original languageEnglish
Article number108492
JournalMolecular Genetics and Metabolism
Publication statusPublished - Jun 2024


  • Development
  • Early development
  • O-GlcNAc
  • Patient derived IPSCs


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