An O-GlcNAc transferase pathogenic variant that affects pluripotent stem cell self-renewal

Omelkova, M.; Fenger, C. D.; Murray, M.; Hammer, T. B.; Pravata, V. M.; Bartual, S.; Czajewski, I.; Bayat, A.; Ferenbach, A. T.; Stavridis, M.; van Aalten, D. M. F.

doi:10.1101/2023.03.13.531514

bioRxiv · 10.1101/2023.03.13.531514

An O-GlcNAc transferase pathogenic variant that affects pluripotent stem cell self-renewal

Omelkova, M.·Fenger, C. D.·Murray, M.·Hammer, T. B.·Pravata, V. M.·Bartual, S.·Czajewski, I.·Bayat, A.·Ferenbach, A. T.·Stavridis, M.·van Aalten, D. M. F.

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Abstract

O-linked {beta}-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 Disorder of Glycosylation (OGT-CDG) which is characterized by X-linked intellectual disability (XLID) and developmental delay. Here, we report an OGTC921Y variant which co-segregates with XLID and epileptic seizures, and results in loss of catalytic activity. Colonies formed by mouse embryonic stem cells carrying OGTC921Y show decreased levels of protein O-GlcNAcylation accompanied by decreased levels of Oct4, 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. Summary statementWe show that the C921Y O-GlcNAc transferase variant found in patients with intellectual disability leads to a defect in pluripotent stem cell self-renewal and decreased levels of stem cell markers.

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Omelkova, M., Fenger, C. D., Murray, M., Hammer, T. B., Pravata, V. M., Bartual, S., Czajewski, I., Bayat, A., Ferenbach, A. T., Stavridis, M., van Aalten, D. M. F.. 2023-03-13. An O-GlcNAc transferase pathogenic variant that affects pluripotent stem cell self-renewal. https://doi.org/10.1101/2023.03.13.531514

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