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

doi:10.1242/dmm.049132

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

DArcy Thompson Unit

Research output: Contribution to journal › Article › peer-review

8 Citations (Scopus)

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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 disorder 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 language	English
Article number	dmm049132
Number of pages	13
Journal	Disease Models and Mechanisms (DMM)
Volume	16
Issue number	6
Early online date	19 Jun 2023
DOIs	https://doi.org/10.1242/dmm.049132
Publication status	Published - Jun 2023

Keywords

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

ASJC Scopus subject areas

Immunology and Microbiology (miscellaneous)
General Biochemistry,Genetics and Molecular Biology
Neuroscience (miscellaneous)
Medicine (miscellaneous)

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10.1242/dmm.049132Licence: CC BY

Final Published VersionFinal published version, 4.95 MBLicence: CC BY

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Omelková, M., Fenger, C. D., Murray, M., Hammer, T. B., Pravata, V. M., Bartual, S. G., Czajewski, I., Bayat, A., Ferenbach, A. T., Stavridis, M. P., & van Aalten, D. M. F. (2023). An O-GlcNAc transferase pathogenic variant linked to intellectual disability affects pluripotent stem cell self-renewal. Disease Models and Mechanisms (DMM), 16(6), Article dmm049132. https://doi.org/10.1242/dmm.049132

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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 disorder 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.",

keywords = "Congenital disorders of glycosylation, Intellectual disability, O-GlcNAc, OGT, Self-renewal, Stem cells",

author = "Michaela Omelkov{\'a} and Fenger, {Christina D{\"u}hring} and Marta Murray and Hammer, {Trine Bj{\o}rg} and Pravata, {Veronica M.} and Bartual, {Sergio Galan} and Ignacy Czajewski and Allan Bayat and Ferenbach, {Andrew T.} and Stavridis, {Marios P.} and {van Aalten}, {Daan M. F.}",

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doi = "10.1242/dmm.049132",

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Omelková, M, Fenger, CD, Murray, M, Hammer, TB, Pravata, VM, Bartual, SG, Czajewski, I, Bayat, A, Ferenbach, AT, Stavridis, MP & van Aalten, DMF 2023, 'An O-GlcNAc transferase pathogenic variant linked to intellectual disability affects pluripotent stem cell self-renewal', Disease Models and Mechanisms (DMM), vol. 16, no. 6, dmm049132. https://doi.org/10.1242/dmm.049132

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AU - Omelková, Michaela

AU - Fenger, Christina Dühring

AU - Murray, Marta

AU - Hammer, Trine Bjørg

AU - Pravata, Veronica M.

AU - Bartual, Sergio Galan

AU - Czajewski, Ignacy

AU - Bayat, Allan

AU - Ferenbach, Andrew T.

AU - Stavridis, Marios P.

AU - van Aalten, Daan M. F.

PY - 2023/6

Y1 - 2023/6

N2 - 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 disorder 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.

AB - 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 disorder 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.

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

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Modelling O-GlcNAc Transferase Intellectual Disability in Drosophila (PhD Studentship)

Molecular and Cellular Biology 4 Year PhD Studentships

Flow Cytometry and Cell Sorting

Cite this

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

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Projects

Modelling O-GlcNAc Transferase Intellectual Disability in Drosophila (PhD Studentship)

Molecular and Cellular Biology 4 Year PhD Studentships

Equipment

Flow Cytometry and Cell Sorting

Cite this