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

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.

Genetic and Protein Network Underlying the Convergence of Rett-Syndrome-like (RTT-L) Phenotype in Neurodevelopmental Disorders

“…This mutation was reported previously to be associated with childhood febrile seizures [52]. Patient 2 carries a heterozygous de novo mutation in the GRIN1 gene, which is associated with neurodevelopmental disorders involving seizures [53,54]. The heterozygous c.2443G>C substitution resulted in a missense mutation (p. Gly815Arg; CADD PHRED score: 34).…”

Expanding the Phenotypic Spectrum of GRIN1 Encephalopathy: Two Pediatric Patients with Atypical Findings

“…GRIN1 encephalopathy is an emerging genetic entity due to de novo monoallelic or biallelic pathogenic variants in the GRIN1 gene that impair the function of the GluN1 subunit of the NMDAR. 6,9,10 It was first described in patients with nonsyndromic intellectual disability and epileptic encephalopathy. Currently, the clinical presentation is widely variable, but the main characteristics are the presence of severe developmental delay and intellectual disability, hypotonia leading to spastic quadriparesis, hyperkinetic movement disorders, and oculomotor abnormalities, as well as cortical visual impairment.…”

Advances toward precision therapeutics for developmental and epileptic encephalopathies

“…First, some of the genetic rodent models generated so far do not show epileptic activity, e.g., Cdkl5 gene knockout or mutated mice ( Fallah and Eubanks, 2020 ) or most of the viable mouse models carrying mutation/deletion in one of the genes coding for the different NMDA receptor subunits: Grin1 , Grin2a , Grin2b , or Grin2d ( Oyrer et al, 2018 ). These last rodent models are generated to mimic GRIN -related disorders, also called “grinpathies” ( Santos-Gómez et al, 2021 ). Compared to rodent models, the alterations of GRIN genes in humans have a much more important impact, considering that they are often dominant ( XiangWei et al, 2018 ).…”