Pathogenic O-GlcNAc dyshomeostasis is associated with cortical malformations and hyperactivity.

Pathogenic O-GlcNAc dyshomeostasis linked to neurodevelopmental defects and behavioral abnormalities in a rodent model of OGT-ID.

• Why it matters: Understanding how OGT mutations cause intellectual disability is crucial for developing targeted therapies, as the mechanisms connecting protein modification to brain development remain unclear.
• What they did: Researchers analyzed a rodent model with the C921Y OGT variant, examining behavior, brain structure via imaging, histology, and proteomics to uncover developmental and molecular disruptions.
• The result: Findings show neurodevelopmental defects, including microcephaly and cortical dysplasia, driven by O-GlcNAc imbalance, which underpins behavioral deficits and offers insights for future treatments.