Pathogenic O-GlcNAc dyshomeostasis is associated with cortical malformations and hyperactivity
Missense variants in the O-GlcNAc transferase ( OGT ) gene have recently been shown to segregate with a syndromic form of intellectual disability (OGT-ID), underscoring the importance of protein O-GlcNAcylation in brain function. However, the underlying pathophysiological mechanisms linking ID to potential OGT malfunction—whether developmental, neurophysiological, or both – remain unclear. Here,…
A study has uncovered a link between pathogenic O-GlcNAc dyshomeostasis and cortical malformations, as well as hyperactivity, in a rodent model carrying a specific OGT-ID variant. O-GlcNAc transferase (OGT) gene missense variants have been linked to a syndromic form of intellectual disability (OGT-ID), highlighting the importance of protein O-GlcNAcylation in brain function.
However, the mechanisms connecting ID to potential OGT malfunction are not fully understood. In this study, mice with the pathogenic C921Y OGT-ID variant exhibited various behavioral issues, such as hyperactivity, impulsivity, and associative learning problems. Structural imaging techniques, including micro-computed tomography and magnetic resonance imaging, uncovered reduced skull size, microcephaly, thinner cortices, and underdeveloped corpus callosums.
Histological examination of the neocortex revealed abnormal growth patterns, primarily impacting the cingulate cortex's superficial layers. Further investigation using quantitative proteomic analyses identified O-GlcNAc dyshomeostasis linked to specific molecular pathways essential for brain development. These findings suggest neurodevelopmental defects associated with O-GlcNAc dyshomeostasis and establish a foundation for exploring the underlying mechanisms and potential treatments for OGT-ID.
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