[en] Genetic variants in the genes GRIN1, GRIN2A, GRIN2B, and GRIN2D, which encode subunits of the N-methyl-D-aspartate receptor (NMDAR), have been associated with severe and heterogeneous neurologic and neurodevelopmental disorders, including early onset epilepsy, developmental and epileptic encephalopathy, intellectual disability, and autism spectrum disorders. Missense variants in these genes can result in gain or loss of the NMDAR function, requiring opposite therapeutic treatments. Computational methods that predict pathogenicity and molecular functional effects of missense variants are therefore crucial for therapeutic applications. We assembled 223 missense variants from patients, 631 control variants from the general population, and 160 missense variants characterized by electrophysiological readouts that show whether they can enhance or reduce the function of the receptor. This includes new functional data from 33 variants reported here, for the first time. By mapping these variants onto the NMDAR protein structures, we found that pathogenic/benign variants and variants that increase/decrease the channel function were distributed unevenly on the protein structure, with spatial proximity to ligands bound to the agonist and antagonist binding sites being a key predictive feature for both variant pathogenicity and molecular functional consequences. Leveraging distances from ligands, we developed two machine-learning based predictors for NMDA variants: a pathogenicity predictor which outperforms currently available predictors and the first molecular function (increase/decrease) predictor. Our findings can have direct application to patient care by improving diagnostic yield for genetic neurodevelopmental disorders and by guiding personalized treatment informed by the knowledge of the molecular disease mechanism.
Research center :
Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group)
Montanucci, Ludovica ; Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, 1133 John Freeman Blvd, Houston, TX 77030, United States
Brünger, Tobias; Cologne Center for Genomics, University of Cologne, University Hospital Cologne, Weyertal 115b, Cologne 50937, Germany
Bhattarai, Nisha; Epilepsy Center, Neurological Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44106, United States
Boßelmann, Christian M; Epilepsy Center, Neurological Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44106, United States
Kim, Sukhan; Department of Pharmacology and Chemical Biology, Emory University School of Medicine, 100 Woodruff Circle, Atlanta, GA 30322, United States ; Center for Functional Evaluation of Rare Variants (CFERV), Emory University School of Medicine, 100 Woodruff Circle, Atlanta, GA 30322, United States
Allen, James P; Department of Pharmacology and Chemical Biology, Emory University School of Medicine, 100 Woodruff Circle, Atlanta, GA 30322, United States
Zhang, Jing; Department of Pharmacology and Chemical Biology, Emory University School of Medicine, 100 Woodruff Circle, Atlanta, GA 30322, United States
Klöckner, Chiara; Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Philipp-Rosenthal-street 55, Leipzig 04103, Germany
Krey, Ilona; Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Philipp-Rosenthal-street 55, Leipzig 04103, Germany
Fariselli, Piero; Department of Medical Sciences, University of Torino, Via Santena 19,Torino, 10123, Italy
MAY, Patrick ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core
Lemke, Johannes R; Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Philipp-Rosenthal-street 55, Leipzig 04103, Germany
Myers, Scott J; Department of Pharmacology and Chemical Biology, Emory University School of Medicine, 100 Woodruff Circle, Atlanta, GA 30322, United States ; Center for Functional Evaluation of Rare Variants (CFERV), Emory University School of Medicine, 100 Woodruff Circle, Atlanta, GA 30322, United States
Yuan, Hongjie; Department of Pharmacology and Chemical Biology, Emory University School of Medicine, 100 Woodruff Circle, Atlanta, GA 30322, United States ; Center for Functional Evaluation of Rare Variants (CFERV), Emory University School of Medicine, 100 Woodruff Circle, Atlanta, GA 30322, United States
Traynelis, Stephen F ; Department of Pharmacology and Chemical Biology, Emory University School of Medicine, 100 Woodruff Circle, Atlanta, GA 30322, United States ; Center for Functional Evaluation of Rare Variants (CFERV), Emory University School of Medicine, 100 Woodruff Circle, Atlanta, GA 30322, United States
Lal, Dennis; Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, 1133 John Freeman Blvd, Houston, TX 77030, United States ; Epilepsy Center, Neurological Institute, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44106, United States ; Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology (M.I.T.) and Harvard, 415 Main St, Cambridge, MA 02142, United States ; Stanley Center for Psychiatric Research, Broad Institute of Harvard and M.I.T, 415 Main St., Cambridge, MA 02142, United States
FNR16394868 - Epileptogenesis Of Genetic Epilepsies, 2021 (01/10/2021-...) - Alexander Skupin
Name of the research project :
U-AGR-7124 - INTER/DFG/21/16394868/MechEPI2 - SKUPIN Alexander
Funders :
FNR - Fonds National de la Recherche BMBF - Federal Ministry of Education and Research
Funding text :
This work was supported by a grant from SFARI (732132 to SFT, TAB, JL). This work was supported by NS111619 (ST), HD082373 (HY), and AG072142 (SJM). Funding for this work was provided from the German Federal Ministry for Education and Research (BMBF) to DL, TB and PM (Treat-ION, 01GM1907D) and PM (Treat-Ion2, 01GM2210B) and the Fonds National de la Recherche Luxembourg (Research Unit FOR-2715, FNR grant INTER/DFG/21/16394868 MechEPI2) to PM.
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