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Title: Mechanistic insight into NMDA receptor dysregulation by rare variants in the GluN2A and GluN2B agonist binding domains
Austin Authors: Swanger, Sharon A;Wenjuan, Chen;Wells, Gordon;Burger, Pieter B;Tankovic, Anel;Bhattacharya, Subhrajit;Strong, Katie L;Hu, Chun;Kusumoto, Hirofumi;Zhang, Jing;Adams, David R;Millichap, John J;Petrovski, Slavé;Traynelis, Stephen F;Yuan, Hongjie
Affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, GA, USA
Department of Chemistry, Emory University, Atlanta, GA, USA
Undiagnosed Diseases Network, National Human Genome Research Institute, NIH, Bethesda, MD, USA
Departments of Pediatrics and Neurology, Northwestern University Feinberg School of Medicine and Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, USA
Department of Medicine, The University of Melbourne, Austin Health and Royal Melbourne Hospital, Melbourne, Victoria, Australia
Center for Functional Evaluation of Rare Variants (CFERV), Emory University School of Medicine, Atlanta, GA, USA
Issue Date: Dec-2016 2016-11-10
Publication information: American Journal of Human Genetics 2016; 99(6): 1261-1280
Abstract: Epilepsy and intellectual disability are associated with rare variants in the GluN2A and GluN2B (encoded by GRIN2A and GRIN2B) subunits of the N-methyl-D-aspartate receptor (NMDAR), a ligand-gated ion channel with essential roles in brain development and function. By assessing genetic variation across GluN2 domains, we determined that the agonist binding domain, transmembrane domain, and the linker regions between these domains were particularly intolerant to functional variation. Notably, the agonist binding domain of GluN2B exhibited significantly more variation intolerance than that of GluN2A. To understand the ramifications of missense variation in the agonist binding domain, we investigated the mechanisms by which 25 rare variants in the GluN2A and GluN2B agonist binding domains dysregulated NMDAR activity. When introduced into recombinant human NMDARs, these rare variants identified in individuals with neurologic disease had complex, and sometimes opposing, consequences on agonist binding, channel gating, receptor biogenesis, and forward trafficking. Our approach combined quantitative assessments of these effects to estimate the overall impact on synaptic and non-synaptic NMDAR function. Interestingly, similar neurologic diseases were associated with both gain- and loss-of-function variants in the same gene. Most rare variants in GluN2A were associated with epilepsy, whereas GluN2B variants were associated with intellectual disability with or without seizures. Finally, discerning the mechanisms underlying NMDAR dysregulation by these rare variants allowed investigations of pharmacologic strategies to correct NMDAR function.
DOI: 10.1016/j.ajhg.2016.10.002
PubMed URL:
Type: Journal Article
Subjects: Receptors, N-Methyl-D-Aspartate
Appears in Collections:Journal articles

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