An O-GlcNAc transferase pathogenic variant linked to intellectual disability affects pluripotent stem cell self-renewal

Michaela Omelková, Christina Dühring Fenger, Marta Murray, Trine Bjørg Hammer, Veronica M. Pravata, Sergio Galan Bartual, Ignacy Czajewski, Allan Bayat, Andrew T. Ferenbach, Marios P. Stavridis, Daan M.F. van Aalten*

*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

Abstract

O-linked β-N-acetylglucosamine (O-GlcNAc) transferase (OGT) is an essential enzyme that modifies proteins with O-GlcNAc. Inborn OGT genetic variants were recently shown to mediate a novel type of congenital hdisorder of glycosylation (OGT-CDG), which is characterised by X-linked intellectual disability (XLID) and developmental delay. Here, we report an OGTC921Y variant that co-segregates with XLID and epileptic seizures, and results in loss of catalytic activity. Colonies formed by mouse embryonic stem cells carrying OGTC921Y showed decreased levels of protein O-GlcNAcylation accompanied by decreased levels of Oct4 (encoded by Pou5f1), Sox2 and extracellular alkaline phosphatase (ALP), implying reduced self-renewal capacity. These data establish a link between OGT-CDG and embryonic stem cell self-renewal, providing a foundation for examining the developmental aetiology of this syndrome.

Original languageEnglish
Article numberdmm049132
JournalDMM Disease Models and Mechanisms
Volume16
Issue6
Number of pages13
ISSN1754-8403
DOIs
Publication statusPublished - Jun 2023

Keywords

  • Congenital disorders of glycosylation
  • Intellectual disability
  • O-GlcNAc
  • OGT
  • Self-renewal
  • Stem cells

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