biostudies-literatureCzajewski INovo Nordisk FoundationNational Centre for the Replacement, Refinement and Reduction of Animals in ResearchVillum FondenNovo Nordisk Foundation Center for Basic Metabolic ResearchWellcome Truste90376https://www.ebi.ac.uk/biostudies/studies/S-EPMC11623933biostudies-literatureUnknown13O-GlcNAcylation is an essential intracellular protein modification mediated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Recently, missense mutations in <i>OGT</i> have been linked to intellectual disability, indicating that this modification is important for the development and functioning of the nervous system. However, the processes that are most sensitive to perturbations in O-GlcNAcylation remain to be identified. Here, we uncover quantifiable phenotypes in the fruit fly <i>Drosophila melanogaster</i> carrying a patient-derived OGT mutation in the catalytic domain. Hypo-O-GlcNAcylation leads to defects in synaptogenesis and reduced sleep stability. Both these phenotypes can be partially rescued by genetically or chemically targeting OGA, suggesting that a balance of OGT/OGA aceLifeRescuable sleep and synaptogenesis phenotypes in a &lt;i&gt;Drosophila&lt;/i&gt; model of O-GlcNAc transferase intellectual disability.PMC11623933Villum Investigator 00054496NNF21OC0065969T001682110061van Aalten DMFCzajewski ISwain BMcDowall LFerenbach ATXu JfalseRescuable sleep and synaptogenesis phenotypes in a &lt;i&gt;Drosophila&lt;/i&gt; model of O-GlcNAc transferase intellectual disability.O-GlcNAcylation is an essential intracellular protein modification mediated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). Recently, missense mutations in <i>OGT</i> have been linked to intellectual disability, indicating that this modification is important for the development and functioning of the nervous system. However, the processes that are most sensitive to perturbations in O-GlcNAcylation remain to be identified. Here, we uncover quantifiable phenotypes in the fruit fly <i>Drosophila melanogaster</i> carrying a patient-derived OGT mutation in the catalytic domain. Hypo-O-GlcNAcylation leads to defects in synaptogenesis and reduced sleep stability. Both these phenotypes can be partially rescued by genetically or chemically targeting OGA, suggesting that a balance of OGT/OGA ac2024-01-01T00:00:00Z2024 Nov2025-04-04T01:24:17.928Z2025-04-04T01:24:17.928ZS-EPMC116239333953517510.7554/eLife.90376