{Reference Type}: Journal Article
{Title}: Neuroectoderm phenotypes in a human stem cell model of O-GlcNAc transferase associated with intellectual disability.
{Author}: Murray M;Davidson L;Ferenbach AT;Lefeber D;van Aalten DMF;
{Journal}: Mol Genet Metab
{Volume}: 142
{Issue}: 2
{Year}: 2024 Jun 8
{Factor}: 4.204
{DOI}: 10.1016/j.ymgme.2024.108492
{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.