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 (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

Abstract

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
Early online date8 May 2024
DOIs
Publication statusE-pub ahead of print - 8 May 2024

Keywords

  • O-GlcNAc
  • OGT-CDG
  • development
  • patient derived IPSCs
  • early development

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