Year: 2026
Type: preprint
Abstract: Pathogenic variants in O-GlcNAc transferase, which catalyses nucleocytoplasmic protein O-GlcNAcylation, cause a neurodevelopmental disorder (OGT-NDD) characterised by intellectual disability and motor impairments. However, mechanisms linking O-GlcNAc dyshomeostasis to brain development remain unclear. Longitudinal neuroimaging of an individual carrying the p.Asn648Tyr OGT-NDD variant, combined with developmental and molecular analyses of an Ogt N648Y/y mouse model, revealed that the mouse phenocopied the impaired cerebellar growth in the patient. Altered OGT distribution and reduced Calbindin expression preceded reduced Purkinje and granule cell densities and molecular layer thinning, alongside increased microglial density, persistent phagocytic cup-like structures and reduced interleukin (IL)-4 levels. Pharmacological OGT inhibition reduced IL-4-induced reporter activity in vitro , while primary Ogt N648Y/y microglia exhibited blunted IL-4-induced O-GlcNAcylation with enrichment of inflammatory and innate immunity programmes. These findings link impaired OGT catalytic function to postnatal cerebellar maturation during a critical developmental window and identify IL-4-associated microglial responses as a contributor to cerebellar pathology in OGT-NDD.
Source: medRxiv
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7216230118