与智力障碍相关的O-GlcNAc转移酶人类干细胞模型的神经外胚层表型

IF 3.7 2区 生物学 Q2 ENDOCRINOLOGY & METABOLISM Molecular genetics and metabolism Pub Date : 2024-05-08 DOI:10.1016/j.ymgme.2024.108492
Marta Murray , Lindsay Davidson , Andrew T. Ferenbach , Dirk Lefeber , Daan M.F. van Aalten
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引用次数: 0

摘要

O-GlcNAc转移酶基因(OGT)的致病变体与先天性糖基化紊乱(OGT-CDG)有关,表现为智力障碍,可能源于神经外胚层。为了验证病理学与胚胎早期分化缺陷有关的假设,我们开发了一种OGT-CDG诱导多能干细胞系,并通过CRISPR/Cas9基因编辑技术生成了同源对照。虽然OGT-CDG变体导致OGT和O-GlcNAcase蛋白水平显著下降,但分化潜能或干性没有发生变化。然而,分化成外胚层会导致O-GlcNAc平衡出现显著差异。进一步分化为神经元干细胞后,发现患者和对照品系的形态存在差异,同时O-GlcNAc通路也受到破坏。这表明O-GlcNAcylation在早期神经外胚层结构中起着关键作用,在干细胞分化的最初阶段具有强大的补偿机制。
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Neuroectoderm phenotypes in a human stem cell model of O-GlcNAc transferase associated with intellectual disability

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.

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来源期刊
Molecular genetics and metabolism
Molecular genetics and metabolism 生物-生化与分子生物学
CiteScore
5.90
自引率
7.90%
发文量
621
审稿时长
34 days
期刊介绍: Molecular Genetics and Metabolism contributes to the understanding of the metabolic and molecular basis of disease. This peer reviewed journal publishes articles describing investigations that use the tools of biochemical genetics and molecular genetics for studies of normal and disease states in humans and animal models.
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