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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\n                    <jats:italic>GRIN2B<\/jats:italic>\n                    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\u2019s 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\n                    <jats:italic>GRIN<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1038\/s41398-026-04186-0","type":"journal-article","created":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T07:55:30Z","timestamp":1782287730000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Clinic-to-Mechanism: Unraveling in-depth molecular dysfunctions caused by a GluN2B C-Terminal deletion in developmental and epileptic encephalopathies"],"prefix":"10.1038","volume":"16","author":[{"given":"Roza","family":"Szlendak","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4827-7303","authenticated-orcid":false,"given":"Nathalie","family":"Bouquier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sylwia","family":"Rzo\u0144ca-Niewczas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annie","family":"Varrault","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tristan","family":"Bouschet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariola","family":"Rudzka-Dyba\u0142a","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paulina","family":"G\u00f3rka-Skoczylas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Lory","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dorota","family":"Hoffman-Zacharska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6199-0448","authenticated-orcid":false,"given":"Julie","family":"Perroy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,24]]},"reference":[{"key":"4186_CR1","first-page":"641","volume":"75","author":"J Davies","year":"1979","unstructured":"Davies J, Evans RH, Francis AA, Watkins JC. 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Institutional bioethical committee approved this study (nr 14\/2019 from 04.04.2019). The Department of Medical Genetics at the Institute of Mother and Child holds authorization from the Polish Ministry of Climate and Environment (Decision No. 116\/2023; permit valid indefinitely) for the contained use of genetically modified microorganisms, organisms, tissues, or cells (GMMs\/GMOs). Patient\u2019s parents signed the informed consent for both the diagnostic investigation of the disease and the skin biopsy procedure.","order":2,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Ethics"}}],"article-number":"457"}}