Glutamatergic neurotransmission is crucial for brain development, wiring neuronal function, and synaptic plasticity mechanisms. Recent genetic studies showed the existence of autosomal dominant de novo GRIN gene variants associated with GRINrelated disorders (GRDs), a rare pediatric neurological disorder caused by N-methyl-D-aspartate receptor (NMDAR) dysfunction. Notwithstanding, GRIN variants identification is exponentially growing and their clinical, genetic, and functional annotations remain highly fragmented, representing a bottleneck in GRD patient's stratification. To shorten the gap between GRIN variant identification and patient stratification, we present the GRIN database (GRINdb), a publicly available, nonredundant, updated, and curated database gathering all available genetic, functional, and clinical data from more than 4000 GRIN variants. The manually curated GRINdb outputs on a web server, allowing query and retrieval of reported GRIN variants, and thus representing a fast and reliable bioinformatics resource for molecular clinical advice. Furthermore, the comprehensive mapping of GRIN variants' genetic and clinical information along NMDAR structure revealed important differences in GRIN variants' pathogenicity and clinical phenotypes, shedding light on GRIN-specific fingerprints. Overall, the GRINdb and web server is a resource for molecular stratification of GRIN variants, delivering clinical and investigational insights into GRDs.
Internal water molecules play an essential role in the structure and function of membrane proteins including G protein-coupled receptors (GPCRs). However, technical limitations severely influence the number and certainty of observed water molecules in 3D structures. This may compromise the accuracy of further structural studies such as docking calculations or molecular dynamics simulations. Here we present HomolWat, a web application for incorporating water molecules into GPCR structures by using template-based modelling of homologous water molecules obtained from high-resolution structures. While there are various tools available to predict the positions of internal waters using energy-based methods, the approach of borrowing lacking water molecules from homologous GPCR structures makes HomolWat unique. The tool can incorporate water molecules into a protein structure in about a minute with around 85% of water recovery. The web server is freely available at http://lmc.uab.es/homolwat.
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 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 on 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.
The massive amount of data generated from genome sequencing brings tons of newly identified mutations, whose pathogenic/non-pathogenic effects need to be evaluated. This has given rise to several mutation predictor tools that, in general, do not consider the specificities of the various protein groups. We aimed to develop a predictor tool dedicated to membrane proteins, under the premise that their specific structural features and environment would give different responses to mutations compared to globular proteins. For this purpose, we created TMSNP, a database that currently contains information from 2624 pathogenic and 196 705 non-pathogenic reported mutations located in the transmembrane region of membrane proteins. By computing various conservation parameters on these mutations in combination with annotations, we trained a machine-learning model able to classify mutations as pathogenic or not. TMSNP (freely available at http://lmc.uab.es/tmsnp/) improves considerably the prediction power of commonly used mutation predictors trained with globular proteins.
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