TY - JOUR
T1 - Neuroectoderm phenotypes in a human stem cell model of O-GlcNAc transferase associated with intellectual disability
AU - Murray, Marta
AU - Davidson, Lindsay
AU - Ferenbach, Andrew T.
AU - Lefeber, Dirk
AU - van Aalten, Daan M.F.
N1 - Publisher Copyright:
© 2024
PY - 2024/6
Y1 - 2024/6
N2 - 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.
AB - 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.
KW - Development
KW - Early development
KW - O-GlcNAc
KW - OGT-CDG
KW - Patient derived IPSCs
UR - http://www.scopus.com/inward/record.url?scp=85193060801&partnerID=8YFLogxK
U2 - 10.1016/j.ymgme.2024.108492
DO - 10.1016/j.ymgme.2024.108492
M3 - Review
C2 - 38759397
AN - SCOPUS:85193060801
SN - 1096-7192
VL - 142
JO - Molecular Genetics and Metabolism
JF - Molecular Genetics and Metabolism
IS - 2
M1 - 108492
ER -