Neurodevelopmental defects in a mouse model of O-GlcNAc transferase intellectual disability

O-GlcNAcylation is a protein modification that is critical for vertebrate development, catalysed by O-GlcNAc transferase (OGT) and reversed by O-GlcNAcase (OGA). Missense mutations in OGT have recently been shown to segregate with a syndromic form of intellectual disability, OGT-linked Congenital Disorder of Glycosylation (OGT-CDG). Although OGT-CDG suggests a critical role of O-GlcNAcylation in neurodevelopment and/or cognitive function, the underlying pathophysiologic mechanisms remain unknown. Here we report three mouse lines that carry three different catalytically impaired OGT-CDG variants. These mice show altered O-GlcNAc homeostasis with decreased global O-GlcNAcylation and OGT/OGA levels in the brain. Phenotypic characterization of the mice revealed microcephaly and cognitive deficits including hyperactivity, anxiety and altered spatial working memory. These mouse models will serve as an important tool to study genotype-phenotype correlation in OGT-CDG in vivo and for the development of possible treatment avenues for this disorder. Significant statementMutations in O-GlcNAc transferase (OGT), the sole enzyme that installs O-GlcNAc sugar on proteins, lead to intellectual disability through unknown mechanisms. We have generated mouse models carrying OGT mutations that show reduction in brain size, hyperactivity and defects in memory. These mouse models will serve as a valuable tool to further investigate disease mechanism and propose future treatment avenues.