Disease-associated GRIN protein truncating variants trigger NMDA receptor loss-of-function

The data presented contribute to delineate GRIN PTVs genotype-phenotype association and GRIN variants stratification

Ana Santos-Gómez 1Federico Miguez-Cabello 2 3Adrián García-Recio 1 4Sílvia Locubiche-Serra 1 5Roberto García-Díaz 2 6 7Víctor Soto-Insuga 8Rosa Guerrero-López 9Natalia Juliá-Palacios 10Francisco Ciruela 1 11Àngels García-Cazorla 10David Soto 2 3Mireia Olivella 12 13Xavier Altafaj 1 2 3

1Neuroscience Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, 08908 Barcelona, Spain.

2Neurophysiology Laboratory, Department of Biomedicine, Faculty of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, 08036 Barcelona, Spain.

3August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Hospital Clínic, University of Barcelona, 08036 Barcelona, Spain.

4Laboratory of Computational Medicine, 08500 Bellaterra, Spain.

5ZeClinics SL, Germans Trias i Pujol Research Institute (IGTP), 08916 Badalona, Spain.

6Chemistry and Biotechnology Research Group (QUIBIO), University of Santiago de Cali, 111321 Cali, Colombia.

7Protein Research Group, Chemistry Department, Colombia National University, Bogotá, Colombia.

8Neurology Service, Hospital Niño Jesús, 28009 Madrid, Spain.

9Instituto de Investigaciones Biomédicas Alberto Sols, CSIC/UAM and Centro de Investigación Biomédica en Red de Enfermedades Raras, CIBERER, 28029 Madrid, Spain.

10Neurometabolic Unit, Department of Neurology. Hospital Sant Joan de Déu and CIBERER, 08950 Barcelona, Spain.

11Department of Pathology and Experimental Therapeutics, Faculty of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, 08908 Barcelona, Spain.

12School of International Studies, ESCI-UPF, 08003 Barcelona, Spain.

13Bioinformatics and Medical Statistics Group. Universitat de Vic-Universitat Central de Catalunya, 08500 Vic, Spain.



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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