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^*

^*Corresponding author af dette arbejde

Institut for Molekylærbiologi og Genetik - Cellulær sundhed, intervention og ernæring

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

8 Citationer (Scopus)

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.

Originalsprog	Engelsk
Artikelnummer	dmm049132
Tidsskrift	DMM Disease Models and Mechanisms
Vol/bind	16
Nummer	6
Antal sider	13
ISSN	1754-8403
DOI	https://doi.org/10.1242/dmm.049132
Status	Udgivet - jun. 2023

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10.1242/dmm.049132Licens: 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. DMM Disease Models and Mechanisms, 16(6), Artikel dmm049132. https://doi.org/10.1242/dmm.049132

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

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.",

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.}",

note = "Publisher Copyright: {\textcopyright} 2023. Published by The Company of Biologists Ltd.",

year = "2023",

month = jun,

doi = "10.1242/dmm.049132",

language = "English",

volume = "16",

journal = "DMM Disease Models and Mechanisms",

issn = "1754-8403",

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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', DMM Disease Models and Mechanisms, bind 16, nr. 6, dmm049132. https://doi.org/10.1242/dmm.049132

An O-GlcNAc transferase pathogenic variant linked to intellectual disability affects pluripotent stem cell self-renewal. / Omelková, Michaela; Fenger, Christina Dühring; Murray, Marta et al.
I: DMM Disease Models and Mechanisms, Bind 16, Nr. 6, dmm049132, 06.2023.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

TY - JOUR

T1 - An O-GlcNAc transferase pathogenic variant linked to intellectual disability affects pluripotent stem cell self-renewal

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

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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 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.

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 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.

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KW - Intellectual disability

KW - O-GlcNAc

KW - OGT

KW - Self-renewal

KW - Stem cells

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U2 - 10.1242/dmm.049132

DO - 10.1242/dmm.049132

M3 - Journal article

C2 - 37334838

AN - SCOPUS:85162652512

SN - 1754-8403

VL - 16

JO - DMM Disease Models and Mechanisms

JF - DMM Disease Models and Mechanisms

IS - 6

M1 - dmm049132

ER -

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

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