Unknown

Dataset Information

0

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.

SUBMITTER: Santos-Gomez A 

PROVIDER: S-EPMC8657601 | biostudies-literature |

REPOSITORIES: biostudies-literature

Similar Datasets

| S-EPMC5837214 | biostudies-literature
| S-EPMC4313871 | biostudies-literature
| S-EPMC5105161 | biostudies-literature
| S-EPMC5109047 | biostudies-literature
| S-EPMC6160549 | biostudies-literature
| S-EPMC6432922 | biostudies-literature
2023-05-24 | GSE216129 | GEO
| S-EPMC7060121 | biostudies-literature
| S-EPMC6251753 | biostudies-literature
| S-EPMC4210299 | biostudies-literature