Mechanistic Insight into NMDA Receptor Dysregulation by Rare Variants in the GluN2A and GluN2B Agonist Binding Domains

Sharon A. Swanger, Wenjuan Chen, Gordon Wells, Pieter B. Burger, Anel Tankovic, Subhrajit Bhattacharya, Katie L. Strong, Chun Hu, Hirofumi Kusumoto, Jing Zhang, David R. Adams, John J. Millichap, Slavé Petrovski, Stephen F. Traynelis*, Hongjie Yuan

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

143 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1261-1280
Number of pages20
JournalAmerican journal of human genetics
Volume99
Issue number6
DOIs
StatePublished - Dec 1 2016

Funding

The authors would like to thank the Exome Aggregation Consortium and the groups that provided exome variant data for comparison. A full list of contributing groups can be found at the ExAC website. The authors also thank Dr. Dennis Liotta for generous support of this study. Research reported in this publication was supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development ( R01HD082373 to H.Y.), the National Center for Advancing Translational Sciences of the NIH ( UL1TR000454 to H.Y.), the National Institute of Neurological Disorders and Stroke ( F32NS086361 to S.A.S. and NS036654 to S.F.T.), and the Xiangya-Emory Medical Schools Visiting Student Program (to W.C.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies. S.F.T. is co-founder of NeurOp Inc., a consultant of Janssen Pharmaceuticals, Pfizer, and NeurOp Inc., and a PI on a research grant from Janssen to Emory University. S.P. serves on the advisory board of Pairnomix.

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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