Abstract
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.
Highlights
Neurodevelopmental disorders (NDDs) result from the disturbance of critical neurodevelopmental processes, caused by the presence of genetic alterations
Despite disease-associated GRIN variants are traditionally dichotomically classified into loss- or gain-of-function variants, functional studies allowed to define GRIN1 variants sub-categories based on dysfunctional NMDARs fingerprints: decreased surface expression of mutant NMDARs, disturbed current density, affected Mg2+ blockade and/or altered NMDAR-mediated currents kinetics
Our study shows the aetiological multiplicity of disease-associated GRIN1 variants and, together with a deep clinical phenotyping, tentatively proposes a genotype-phenotype association of GRIN-related disorders (GRD) severity
Summary
Neurodevelopmental disorders (NDDs) result from the disturbance of critical neurodevelopmental processes, caused by the presence of genetic alterations. Disease-associated variants of GRIN genes (e.g., mostly affecting GRIN1, GRIN2A, GRIN2B and GRIN2D), which encode N-methyl-D-aspartate (NMDA) receptor subunits and oligomerize to form ionotropic glutamate receptors, have been recently associated with rare neurodevelopmental encephalopathies [2,3,4]. The growing number of GRIN variants associated with neurodevelopmental encephalopathies, followed by functional and clinical studies coined the gene-based classification of this group of genetic neurodevelopmental disorders, namely. 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. 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. This structural-functional stratification provides relevant insights of genotypephenotype association, contributing to future precision medicine of GRIN1-related encephalopathies
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