Clinic-to-Mechanism: Unraveling in-depth molecular dysfunctions caused by a GluN2B C-Terminal deletion in developmental and epileptic encephalopathies
Abstract
Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders associated with genetic mutations, including some in GRIN genes encoding NMDA receptor (NMDA-R) subunits. Despite affecting the same receptor, each mutation may lead to distinct neurological disorders, emphasizing the necessity of understanding receptor dysfunction to tailor treatments effectively. In a genetic screen of DEEs patients, we identified a de novo pathogenic GRIN2B nonsense mutation, p.Glu839Ter (called GluN2B-E839*), which truncates the C-terminal domain (CTD) of the GluN2B subunit, a poorly characterized region critical for receptor function. This variant was prioritized for functional study due to the limited knowledge about the CTD's role. We fully characterized the clinical presentation of the patient, who displayed intellectual disability, epilepsy, and hyperkinetic behavioral disorders. Molecular and cellular analyses in heterologous systems and patient-derived neurons revealed that GluN2B-E839* subunit assembles correctly with other subunits to form NMDA-Rs but exhibits reduced surface expression, impaired interactions with PSD95, and altered biophysical properties, including reduced current amplitudes, increased magnesium sensitivity, and diminished calcium influx. These dysfunctions likely contribute to impaired synaptic plasticity and DEEs pathophysiology. Our findings highlight the critical role of the GluN2B CTD in NMDA-R function and neuronal signaling and underscore the need for systematic characterization of GRIN variants to improve diagnostic precision and therapeutic targeting for DEEs. This study establishes a robust framework combining complementary experimental approaches with patient-derived preclinical models to link molecular dysfunctions to clinical phenotypes.
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BibTeX
@article{szlendak2026clinictomechanism,
title = {{Clinic-to-Mechanism: Unraveling in-depth molecular dysfunctions caused by a GluN2B C-Terminal deletion in developmental and epileptic encephalopathies}},
author = {Roza Szlendak and Nathalie Bouquier and Sylwia Rzońca-Niewczas and Annie Varrault and Tristan Bouschet and Mariola Rudzka-Dybała and Paulina Górka-Skoczylas and Philippe Lory and Dorota Hoffman-Zacharska and Julie Perroy},
journal = {Translational Psychiatry},
year = {2026},
month = jun,
doi = {10.1038/s41398-026-04186-0},
url = {https://hal.science/hal-05676993v2},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Clinic-to-Mechanism: Unraveling in-depth molecular dysfunctions caused by a GluN2B C-Terminal deletion in developmental and epileptic encephalopathies
AU - Roza Szlendak
AU - Nathalie Bouquier
AU - Sylwia Rzońca-Niewczas
AU - Annie Varrault
AU - Tristan Bouschet
AU - Mariola Rudzka-Dybała
AU - Paulina Górka-Skoczylas
AU - Philippe Lory
AU - Dorota Hoffman-Zacharska
AU - Julie Perroy
PY - 2026
DA - 2026/06/24
JO - Translational Psychiatry
DO - 10.1038/s41398-026-04186-0
UR - https://hal.science/hal-05676993v2
AB - Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders associated with genetic mutations, including some in GRIN genes encoding NMDA receptor (NMDA-R) subunits. Despite affecting the same receptor, each mutation may lead to distinct neurological disorders, emphasizing the necessity of understanding receptor dysfunction to tailor treatments effectively. In a genetic screen of DEEs patients, we identified a de novo pathogenic GRIN2B nonsense mutation, p.Glu839Ter (called GluN2B-E839*), which truncates the C-terminal domain (CTD) of the GluN2B subunit, a poorly characterized region critical for receptor function. This variant was prioritized for functional study due to the limited knowledge about the CTD's role. We fully characterized the clinical presentation of the patient, who displayed intellectual disability, epilepsy, and hyperkinetic behavioral disorders. Molecular and cellular analyses in heterologous systems and patient-derived neurons revealed that GluN2B-E839* subunit assembles correctly with other subunits to form NMDA-Rs but exhibits reduced surface expression, impaired interactions with PSD95, and altered biophysical properties, including reduced current amplitudes, increased magnesium sensitivity, and diminished calcium influx. These dysfunctions likely contribute to impaired synaptic plasticity and DEEs pathophysiology. Our findings highlight the critical role of the GluN2B CTD in NMDA-R function and neuronal signaling and underscore the need for systematic characterization of GRIN variants to improve diagnostic precision and therapeutic targeting for DEEs. This study establishes a robust framework combining complementary experimental approaches with patient-derived preclinical models to link molecular dysfunctions to clinical phenotypes.
SN - 2158-3188
SN - 2158-3188
ER -