Zscan4 as a candidate conveyor of early developmental defects in O-GlcNAc transferase intellectual disability

TY - JOUR

T1 - Zscan4 as a candidate conveyor of early developmental defects in O-GlcNAc transferase intellectual disability

AU - Pravata, Veronica M.

AU - Jiang, Hao

AU - Ferenbach, Andrew T.

AU - Lamond, Angus

AU - van Aalten, Daan M. F.

N1 - Copyright: © 2025 The Authors. Published by Elsevier Inc. All rights reserved.

PY - 2025/11

Y1 - 2025/11

N2 - Variants in the human β-N-acetylglucosamine (O-GlcNAc) transferase (OGT) gene give rise to an intellectual disability (ID) syndrome termed OGT congenital disorder of glycosylation (OGT-CDG). The mechanisms by which loss of OGT and/or protein O-GlcNAcylation leads to this syndrome are not understood, but symptoms associated with the syndrome suggest a developmental origin. Here, we establish and characterize two lines of mouse embryonic stem cells carrying different patient mutations and show that these mutations lead to disrupted O-GlcNAc homeostasis. Using quantitative proteomics on these cells in the pluripotent state, we identify candidate proteins/pathways that could underpin this syndrome. In addition to the increased levels of OGT and decreased levels of OGA reflecting disrupted O-GlcNAc homeostasis, we find that expression of the ID gene Zscan4 is upregulated. This is associated with increased levels of the OGT:10 Eleven (Tet) - protein complex that regulates DNA methylation and Zscan4 expression. These data uncover a potential mechanism contributing to the developmental aspects of OGT-CDG.

AB - Variants in the human β-N-acetylglucosamine (O-GlcNAc) transferase (OGT) gene give rise to an intellectual disability (ID) syndrome termed OGT congenital disorder of glycosylation (OGT-CDG). The mechanisms by which loss of OGT and/or protein O-GlcNAcylation leads to this syndrome are not understood, but symptoms associated with the syndrome suggest a developmental origin. Here, we establish and characterize two lines of mouse embryonic stem cells carrying different patient mutations and show that these mutations lead to disrupted O-GlcNAc homeostasis. Using quantitative proteomics on these cells in the pluripotent state, we identify candidate proteins/pathways that could underpin this syndrome. In addition to the increased levels of OGT and decreased levels of OGA reflecting disrupted O-GlcNAc homeostasis, we find that expression of the ID gene Zscan4 is upregulated. This is associated with increased levels of the OGT:10 Eleven (Tet) - protein complex that regulates DNA methylation and Zscan4 expression. These data uncover a potential mechanism contributing to the developmental aspects of OGT-CDG.

KW - neurodevelopment

KW - O-GlcNAc transferase

KW - O-GlcNAcylation

KW - OGT-CDG

KW - pluripotency

KW - TET

UR - https://www.scopus.com/pages/publications/105024137982

U2 - 10.1016/j.mcpro.2025.101077

DO - 10.1016/j.mcpro.2025.101077

M3 - Article

C2 - 41033462

SN - 1535-9476

VL - 24

SP - 1

EP - 14

JO - Molecular & Cellular Proteomics

JF - Molecular & Cellular Proteomics

IS - 11

M1 - 101077

ER -