Exploiting O-GlcNAc dyshomeostasis to screen O-GlcNAc transferase intellectual disability variants

TY - JOUR

T1 - Exploiting O-GlcNAc dyshomeostasis to screen O-GlcNAc transferase intellectual disability variants

AU - Yuan, Huijie

AU - Mitchell, Conor W

AU - Ferenbach, Andrew T

AU - Bonati, Maria Teresa

AU - Feresin, Agnese

AU - Benke, Paul J

AU - Tan, Queenie K G

AU - van Aalten, Daan M F

N1 - Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.

PY - 2025/1/14

Y1 - 2025/1/14

N2 - O-GlcNAcylation is an essential protein modification catalyzed by O-GlcNAc transferase (OGT). Missense variants in OGT are linked to a novel intellectual disability syndrome known as OGT congenital disorder of glycosylation (OGT-CDG). The mechanisms by which OGT missense variants lead to this heterogeneous syndrome are not understood, and no unified method exists for dissecting pathogenic from non-pathogenic variants. Here, we develop a double-fluorescence strategy in mouse embryonic stem cells to measure disruption of O-GlcNAc homeostasis by quantifying the effects of variants on endogenous OGT expression. OGT-CDG variants generally elicited a lower feedback response than wild-type and Genome Aggregation Database (gnomAD) OGT variants. This approach was then used to dissect new putative OGT-CDG variants from pathogenic background variants in other disease-associated genes. Our work enables the prediction of pathogenicity for rapidly emerging de novo OGT-CDG variants and points to reduced disruption of O-GlcNAc homeostasis as a common mechanism underpinning OGT-CDG.

AB - O-GlcNAcylation is an essential protein modification catalyzed by O-GlcNAc transferase (OGT). Missense variants in OGT are linked to a novel intellectual disability syndrome known as OGT congenital disorder of glycosylation (OGT-CDG). The mechanisms by which OGT missense variants lead to this heterogeneous syndrome are not understood, and no unified method exists for dissecting pathogenic from non-pathogenic variants. Here, we develop a double-fluorescence strategy in mouse embryonic stem cells to measure disruption of O-GlcNAc homeostasis by quantifying the effects of variants on endogenous OGT expression. OGT-CDG variants generally elicited a lower feedback response than wild-type and Genome Aggregation Database (gnomAD) OGT variants. This approach was then used to dissect new putative OGT-CDG variants from pathogenic background variants in other disease-associated genes. Our work enables the prediction of pathogenicity for rapidly emerging de novo OGT-CDG variants and points to reduced disruption of O-GlcNAc homeostasis as a common mechanism underpinning OGT-CDG.

KW - Acetylglucosamine/metabolism

KW - Animals

KW - Congenital Disorders of Glycosylation/genetics

KW - Glycosylation

KW - Homeostasis

KW - Humans

KW - Intellectual Disability/genetics

KW - Mice

KW - Mouse Embryonic Stem Cells/metabolism

KW - Mutation, Missense

KW - N-Acetylglucosaminyltransferases/metabolism

KW - O-GlcNAc

KW - neurodevelopment

KW - OGT-CDG

KW - OGT

UR - https://www.scopus.com/pages/publications/85214321129

U2 - 10.1016/j.stemcr.2024.11.010

DO - 10.1016/j.stemcr.2024.11.010

M3 - Journal article

C2 - 39706180

SN - 2213-6711

VL - 20

SP - 102380

JO - Stem Cell Reports

JF - Stem Cell Reports

IS - 1

M1 - 102380

ER -