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bioRxiv · 10.1101/2023.09.18.558285

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

Murray, M.·Davidson, L.·Ferenbach, A. T.·Lefeber, D.·van Aalten, D. M.
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Abstract

Most intellectual disabilities are caused by monogenic variation. Mutations in the O-GlcNAc transferase (OGT) gene have recently been linked to a novel congenital disorder of glycosylation (OGT-CDG), involving symptoms of possible 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 lines together with isogenic controls 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.

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Murray, M., Davidson, L., Ferenbach, A. T., Lefeber, D., van Aalten, D. M.. 2023-09-21. Neuroectoderm phenotypes in a human stem cell model of O-GlcNAc transferase intellectual disability. https://doi.org/10.1101/2023.09.18.558285

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