GRIN1 mutation associated with intellectual disability alters NMDA receptor trafficking and function

• Type of Material: Article
• Authors: Wenjuan Chen, Emory University; Christine Shieh, University of California Los Angeles; Sharon Swanger, Emory University; Anel Tankovic, Emory University; Margaret Au, Cedars-Sinai Medical Center; Marianne McGuire, Baylor College of Medicine; Michele Tagliati, Cedars-Sinai Medical Center; John M. Graham, Cedars-Sinai Medical Center; Suneeta Madan-Khetarpal, University of Pittsburgh; Stephen Traynelis, Emory University; Hongjie Yuan, Emory University; Tyler Mark Pierson, Cedars-Sinai Medical Center
• Language: English
• Date: 2017-06-01
• Publisher: Nature Publishing Group: Open Access Hybrid Model Option B
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 The Japan Society of Human Genetics. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1038/jhg.2017.19
• Title of Journal or Parent Work: Journal of Human Genetics
• ISSN: 1434-5161
• Volume: 62
• Issue: 6
• Start Page: 589
• End Page: 597
• Grant/Funding Information: TMP and CS were funded by the Cedars-Sinai institutional funding program and the Cedars-Sinai Diana and Steve Marienhoff Fashion Industries Guild Endowed Fellowship in Pediatric Neuromuscular Diseases.; During this work, WC was supported by the Xiangya-Emory Medical Schools Visiting Student Program; HY was supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development, NIH-R01HD082373, by the Emory +Children’s Pediatric Center Seed Grant Program, by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1TR000454, by NIH HHSN268201400169P; SFT was supported by NIH-NINDS R01NS036654, R24NS092989 and R01NS092989.
• Keywords: Science & Technology; Life Sciences & Biomedicine; ONSET EPILEPTIC ENCEPHALOPATHY; SUBUNIT; DISORDERS; Genetics & Heredity; Paediatric neurological disorders; ENU-MUTAGENESIS; BEHAVIORS; MG2+; Genetics research; MICE; BINDING-SITE; SCHIZOPHRENIA; CHANNELS
• Research Categories: Biology, Neuroscience; Biology, Genetics; Health Sciences, Pharmacology

Abstract

N-methyl-d-aspartate receptors (NMDARs) play important roles in brain development and neurological disease. We report two individuals with similar dominant de novo GRIN1 mutations (c.1858 G > A and c.1858 G > C; both p.G620R). Both individuals presented at birth with developmental delay and hypotonia associated with behavioral abnormalities and stereotypical movements. Recombinant NMDARs containing the mutant GluN1-G620R together with either GluN2A or GluN2B were evaluated for changes in their trafficking to the plasma membrane and their electrophysiological properties. GluN1-G620R/GluN2A complexes showed a mild reduction in trafficking, a ∼2-fold decrease in glutamate and glycine potency, a strong decrease in sensitivity to Mg 2+ block, and a significant reduction of current responses to a maximal effective concentration of agonists. GluN1-G620R/GluN2B complexes showed significantly reduced delivery of protein to the cell surface associated with similarly altered electrophysiology. These results indicate these individuals may have suffered neurodevelopmental deficits as a result of the decreased presence of GluN1-G620R/GluN2B complexes on the neuronal surface during embryonic brain development and reduced current responses of GluN1-G620R-containing NMDARs after birth. These cases emphasize the importance of comprehensive functional characterization of de novo mutations and illustrates how a combination of several distinct features of NMDAR expression, trafficking and function can be present and influence phenotype.