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

• Published in: Molecular genetics and metabolism Vol. 142; no. 2; p. 108492
• Main Authors: Murray, Marta, Davidson, Lindsay, Ferenbach, Andrew T., Lefeber, Dirk, van Aalten, Daan M.F.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2024
• Subjects: Cell Differentiation; Congenital Disorders of Glycosylation - genetics; Congenital Disorders of Glycosylation - metabolism; Congenital Disorders of Glycosylation - pathology; CRISPR-Cas Systems; Development; Early development; Gene Editing; Glycosylation; Humans; Induced Pluripotent Stem Cells - metabolism; Induced Pluripotent Stem Cells - pathology; Intellectual Disability - genetics; Intellectual Disability - pathology; N-Acetylglucosaminyltransferases - genetics; N-Acetylglucosaminyltransferases - metabolism; Neural Plate - metabolism; Neural Stem Cells - metabolism; Neural Stem Cells - pathology; O-GlcNAc; OGT-CDG; Patient derived IPSCs; Phenotype; Development; OGT-CDG; Patient derived IPSCs; O-GlcNAc; Early development
• ISSN: 1096-7192; 1096-7206
• DOI: 10.1016/j.ymgme.2024.108492

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.