A Pathogenic OGT Mutation Results in Behavioral Phenotypes with Selective Molecular Dysregulation

ABSTRACT: Mutations in O-GlcNAc transferase (OGT) cause OGT-X-linked intellectual disability (OGT-XLID), an emerging neurodevelopmental disorder characterized by intellectual disability, developmental delay, behavioral abnormalities, and impaired language. OGT catalyzes the addition of O-linked β-N-acetylglucosamine (O-GlcNAc), a regulatory post-translational modification of intracellular proteins that is essential for brain development and function. However, how patient-derived OGT variants disrupt OGT function and contribute to disease remains poorly understood. Given the role of the OGT tetratricopeptide repeat (TPR) domain in substrate recognition and protein interactions, we generated a knock-in mouse harboring the pathogenic A319T variant to define its molecular and functional consequences in vivo. OGT-A319T mice were viable and overtly normal but exhibited reduced body weight, increased locomotor activity, and repetitive behavior. OGT and O-GlcNAcase (OGA) abundance and enzymatic activity were unchanged across brain regions, indicating that A319T does not broadly impair O-GlcNAc cycling. Instead, A319T caused selective hypo-O-GlcNAcylation of high-molecular-weight (>100 kDa) proteins in the hippocampus. Quantitative proteomic analysis of the hippocampal OGT interactome identified altered interactions with proteins involved in neurodevelopment, cytoskeletal organization, transcriptional regulation, vesicle transport, and neuronal signaling. Targeted studies of host cell factor 1 (HCF1), a well-characterized OGT substrate and abundant component of the OGT interactome, demonstrated reduced association with OGT-A319T and decreased O-GlcNAcylation of full-length HCF1. A319T also altered HCF1 proteolytic processing across brain regions. Together, these findings demonstrate that a disease-associated TPR-domain variant can selectively disrupt OGT protein interactions and substrate O-GlcNAcylation without reducing intrinsic catalytic activity, supporting impaired substrate recognition as a pathogenic mechanism in OGT-XLID.

ORGANISM(S): Mus musculus

PROVIDER: GSE348679 | GEO | 2026/10/02

REPOSITORIES: GEO