Paradigmatic De Novo GRIN1 Variants Recapitulate Pathophysiological Mechanisms Underlying GRIN1-Related Disorder Clinical Spectrum

Background: GRIN-related disorders (GRD), the so-called grinpathies, is a group of rare encephalopathies caused by mutations affecting GRIN genes (mostly GRIN1, GRIN2A and GRIN2B genes), which encode for the GluN subunit of the N-methyl D-aspartate (NMDA) type ionotropic glutamate receptors. A growi...

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Detalhes bibliográficos
Autores: Santos-Gomez, A, Miguez-Cabello, F, Julia-Palacios, N, Garcia-Navas, D, Soto-Insuga, V, Garcia-Penas, JJ, Fuentes, P, Ibanez-Mico, S, Cuesta, L, Cancho, R, Andreo-Lillo, P, Gutierrez-Aguilar, G, Alonso-Luengo, O, Malaga, I, Hedrera-Fernandez, A, Garcia-Cazorla, A, Soto, D, Olivella, M, Altafaj, X
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Recursos:Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana (FISABIO)
Repositorio:r-FISABIO. Repositorio Institucional de Producción Científica
OAI Identifier:oai:fisabio.fundanetsuite.com:p12755
Acesso em linha:https://fisabio.portalinvestigacion.com/publicaciones/12755
Access Level:acceso abierto
Palavra-chave:GRIN-related disorders
glutamatergic neurotransmission
NMDA receptors
neurodevelopmental disorders
Descrição
Resumo:Background: GRIN-related disorders (GRD), the so-called grinpathies, is a group of rare encephalopathies caused by mutations affecting GRIN genes (mostly GRIN1, GRIN2A and GRIN2B genes), which encode for the GluN subunit of the N-methyl D-aspartate (NMDA) type ionotropic glutamate receptors. A growing number of functional studies indicate that GRIN-encoded GluN1 subunit disturbances can be dichotomically classified into gain- and loss-of-function, although intermediate complex scenarios are often present. Methods: In this study, we aimed to delineate the structural and functional alterations of GRIN1 disease-associated variants, and their correlations with clinical symptoms in a Spanish cohort of 15 paediatric encephalopathy patients harbouring these variants. Results: Patients harbouring GRIN1 disease-associated variants have been clinically deeply-phenotyped. Further, using computational and in vitro approaches, we identified different critical checkpoints affecting GluN1 biogenesis (protein stability, subunit assembly and surface trafficking) and/or NMDAR biophysical properties, and their association with GRD clinical symptoms. Conclusions: Our findings show a strong correlation between GRIN1 variants-associated structural and functional outcomes. This structural-functional stratification provides relevant insights of genotype-phenotype association, contributing to future precision medicine of GRIN1-related encephalopathies.

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