BY OUR PLATFORMS
BY THERAPEUTIC AREA
BY RESEARCH STAGE
10 October 2020
Ana Santos-Gómez 1, Federico Miguez-Cabello 2 3, Adrián García-Recio 1 4, Sílvia Locubiche-Serra 1 5, Roberto García-Díaz 2 6 7, Víctor Soto-Insuga 8, Rosa Guerrero-López 9, Natalia Juliá-Palacios 10, Francisco Ciruela 1 11, Àngels García-Cazorla 10, David Soto 2 3, Mireia Olivella 12 13, Xavier Altafaj 1 2 3
De novo GRIN variants, encoding for the ionotropic glutamate NMDA receptor subunits, have been recently associated with GRIN-related disorders (GRDs), a group of rare paediatric encephalopathies. Current investigational and clinical efforts are focused to functionally stratify GRIN variants, towards precision therapies of this primary disturbance of glutamatergic transmission that affects neuronal function and the brain. In the present study, we aimed to comprehensively delineate the functional outcomes and clinical phenotypes of GRIN protein-truncating variants (PTVs) -accounting for ~ 20% of disease-associated GRIN variants- hypothetically provoking NMDAR hypofunctionality. To tackle this question, we created a comprehensive GRIN PTVs variants database compiling a cohort of 9 individuals harbouring GRIN PTVs, together with previously identified variants, to build-up an extensive GRIN PTVs repertoire composed of 293 unique variants. Genotype-phenotype correlation studies were conducted, followed by cell-based assays of selected paradigmatic GRIN PTVs, allowing their functional annotation. Genetic and clinical phenotypes metaanalysis revealed that heterozygous GRIN1, GRIN2C, GRIN2D, GRIN3A, and GRIN3B PTVs are non-pathogenic. In contrast, heterozygous GRIN2A and GRIN2B PTVs are associated with specific neurological clinical phenotypes in a subunit- and domain-dependent manner. Mechanistically, cell-based assays showed that paradigmatic pathogenic GRIN2A and GRIN2B PTVs result in a decrease of NMDAR surface expression and NMDAR-mediated currents, ultimately leading to NMDAR functional haploinsufficiency. Overall, these findings contribute to delineate GRIN PTVs genotype-phenotype association and GRIN variants stratification. Functional studies showed that GRIN2A and GRIN2B pathogenic PTVs trigger NMDAR hypofunctionality, and thus accelerate therapeutic decisions for this neurodevelopmental condition.
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