Pathogenic O-GlcNAc dyshomeostasis associated with cortical malformations and hyperactivity

TY - JOUR

T1 - Pathogenic O-GlcNAc dyshomeostasis associated with cortical malformations and hyperactivity

AU - Authier, Florence

AU - Jan, Asad

AU - Faress, Islam

AU - Stald Skoven, Christian

AU - Esperon-Abril, Iria

AU - Tharmakulasingam Balasubramaniam, Shagana

AU - Coquelin, Kevin-Sebastien

AU - Nyengaard, Jens R.

AU - Scavenius, Carsten

AU - Attianese, Benedetta

AU - Sevillano-Quispe, Oscar G.

AU - Eskildsen, Simon Fristed

AU - Skovhus Thomsen, Jesper

AU - Hansen, Brian

AU - van Aalten, Daan

PY - 2025/4/7

Y1 - 2025/4/7

N2 - 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 OGlcNAcylation in brain function. However, the underlying pathophysiological mechanisms linking ID to potential OGT malfunction—whether developmental, neurophysiological, or both—remain unclear. Here, we present comprehensive analyses encompassing behaviour and brain architecture in a rodent model carrying the C921Y OGT-ID variant. These mice show a range of behavioural deficits, including hyperactivity, impulsivity, and associative learning phenotypes. Structural studies, using micro-computed tomography and magnetic resonance imaging, revealed reduced skull size, microcephaly, reduced cortical thickness and hypoplastic corpus callosum. These were associated with nodular cortical dysplasia affecting the superficial layers of the cingulate cortex. Mechanistically, quantitative proteomic analyses revealed OGlcNAc dyshomeostasis associated with distinct perturbed molecular pathways involved in brain development. Taken together, these data reveal neurodevelopmental defects associated with O-GlcNAc dyshomeostasis and provide a platform for dissecting mechanism and treatments of OGT-ID.

AB - 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 OGlcNAcylation in brain function. However, the underlying pathophysiological mechanisms linking ID to potential OGT malfunction—whether developmental, neurophysiological, or both—remain unclear. Here, we present comprehensive analyses encompassing behaviour and brain architecture in a rodent model carrying the C921Y OGT-ID variant. These mice show a range of behavioural deficits, including hyperactivity, impulsivity, and associative learning phenotypes. Structural studies, using micro-computed tomography and magnetic resonance imaging, revealed reduced skull size, microcephaly, reduced cortical thickness and hypoplastic corpus callosum. These were associated with nodular cortical dysplasia affecting the superficial layers of the cingulate cortex. Mechanistically, quantitative proteomic analyses revealed OGlcNAc dyshomeostasis associated with distinct perturbed molecular pathways involved in brain development. Taken together, these data reveal neurodevelopmental defects associated with O-GlcNAc dyshomeostasis and provide a platform for dissecting mechanism and treatments of OGT-ID.

KW - Intellectual disability

KW - glycosylation

KW - behaviour

KW - cortical dysplasia

KW - neurodevelopment

U2 - 10.7554/eLife.107170

DO - 10.7554/eLife.107170

M3 - Article

SN - 2050-084X

JO - eLife

JF - eLife

ER -