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.
摘要：
O-GlcNAc转移酶基因（OGT）中的致病变体与先天性糖基化障碍（OGT-CDG）有关，表现为可能是神经外胚层起源的智力残疾。为了检验病理与早期胚胎发生过程中的分化缺陷有关的假设，我们开发了一种OGT-CDG诱导的多能干细胞系,以及通过CRISPR/Cas9基因编辑产生的等基因对照.尽管OGT-CDG变体导致OGT和O-GlcNAcase蛋白水平显著降低，分化潜能或干性没有变化.然而,分化为外胚层导致O-GlcNAc稳态的显着差异。进一步分化为神经元干细胞显示患者和对照组之间的形态差异，伴随着O-GlcNAc途径的破坏。这表明O-GlcNAcylation在早期神经外胚层结构中的关键作用，在干细胞分化的早期阶段具有强大的补偿机制。
