Clinic-to-Mechanism: Unraveling in-depth molecular dysfunctions caused by a GluN2B C-Terminal deletion in developmental and epileptic encephalopathies.

Expanded molecular pathomechanisms of GlyR α2 subunit variants in neurodevelopmental disorders and epileptic encephalopathy

Rare genetic variants in the glycine receptor (GlyR) α2 subunit gene ( GLRA2 ) are associated with autism spectrum disorder, developmental delay, and intellectual disability, often accompanied by microcephaly, language delay or epilepsy. We report detailed structure-function analyses of nine previously uncharacterised GlyR α2 missense variants, including a novel de novo change (p.S285P) linked to epileptic encephalopathy. Using molecular modelling/dynamics simulations, electrophysiology, and immunocytochemistry, we assessed effects of GlyR α2 variants on agonist potency, efficacy, channel gating, and cell-surface trafficking. Five missense variants caused a partial loss-of-function via reduced glycine potency (p.F20S, p.A261T, p.R418Q), reduced glycine efficacy (p.F20S), or faster channel deactivation (p.R323C, p.P369T). By contrast, p.R225C abolished cell-surface expression resulting in a complete loss-of-function . The p.A261T variant also significantly reduced picrotoxin binding, resolving ambiguity in GlyR-PTX interaction models. Additional variants showed an alteration-of-function (p.I232M) or a gain-of-function (p.S285P), combining reduced glycine efficacy with increased potency and spontaneous leak currents. Two variants within the intracellular M3-M4 domain (p.R323C and p.P369T) had enhanced channel deactivation consistent with a loss-of-function , while p.P373L showed no detectable functional deficit. These findings expand the clinical and mechanistic spectrum of GlyR α2 variants, identify a key determinant of picrotoxin binding, and highlight unresolved roles of intracellular protein-protein interaction motifs in GlyR α2 function.

Cross-species analysis of GNB1 I80T encephalopathy: conserved developmental, epileptic and neuronal transcriptome signatures

The integrated analysis establishes the first cross-species model for GNB1E, suggests common neurological mechanisms and molecular pathways linked to GNB1E, and provides a framework for mechanistic and therapeutic studies.

Expanding the Phenotypic and Functional Evidence for KCNK3 as a Neurodevelopmental Disorder Gene: A New Chinese Case and Drosophila Validation.

This study represents the first application of a Drosophila model to demonstrate that KCNK3 functions as a dosage-sensitive regulator of neurodevelopment and position KCNK3 as a candidate gene for molecular screening and pave the way for future functional studies and therapeutic exploration in NDDs.

A case report of a novel de novo variant in PPP2CA causing a neurodevelopmental disorder and epilepsy

The findings support the pathogenicity of this variant and further expand the pathogenic variant spectrum of the PPP2CA gene, and the observed genotype–phenotype correlation provides valuable information for prognosis and genetic counseling.

Dystonia-associated TorsinA-ΔE mutation induces a gain-of-function interaction with XPO1 via its N-Terminal hydrophobic segment

From synaptic dysfunction to targeted intervention: a comprehensive review of STXBP1 encephalopathy and precision therapeutic strategies.

A comprehensive narrative review of studies indexed in PubMed/MEDLINE, Embase, Cochrane Library, ClinicalTrials.gov, and American Epilepsy Society proceedings through January 2026 positions STXBP1-RD as a leading test case for precision medicine in DEEs.