TRANSCRIPTOMIC AND PROTEOMIC ANALYSIS OF A MOUSE MODEL CARRYING A MISSENSE OR FRAMESHIFT VARIANT ASSOCIATED WITH NEURODEVELOPMENTAL DISORDERS

NMDA receptors (NMDARs), encoded by the GRIN gene family, are ionotropic glutamate receptors essential for synaptic transmission and activity-dependent neuronal plasticity underlying learning and memory. Pathogenic GRIN variants are associated with severe neurodevelopmental disorders characterized by intellectual disability, developmental delay, and epilepsy. The majority of reported variants are missense, resulting in amino acid substitution, whereas nonsense and frameshift variants generate premature termination codons. Notably, protein-truncating variants (PTVs) are frequently associated with milder clinical phenotypes than missense variants, although the underlying molecular mechanisms remain poorly understood. Here, we investigate the molecular consequences of two clinically relevant GRIN2B variants located in the transmembrane domain using mouse models: a missense variant (L825V) and a frameshift variant (L825FfsTer15). Comparative analysis of primary neurons revealed a significant reduction in NMDAR surface expression in Grin2b^+/L825fs neurons, while Grin2b^+/L825V neurons were unaffected. Furthermore, mRNA expression of GluN1 and GluN2B was selectively reduced in the brains of Grin2b^+/L825fs mice compared to wild-type and Grin2b^+/L825V mice. Transcriptomic and proteomic analyses revealed broader disruptions in gene and protein expression in Grin2b^+/L825fs mice, including downregulation of core NMDAR components. In summary, our data indicate that a less severe PTV exerts stronger effects on NMDAR expression and global gene regulation than a missense variant. These findings provide new mechanistic insight into genotype–phenotype relationships in GRIN2B-related disorders and contribute to a better understanding of their molecular etiology.