title: GRIN1 mutation associated with intellectual disability alters NMDA receptor trafficking and function.
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 Mg2+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.
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, GA, USA.|Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Chen
authors.affiliation: David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Shieh
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Swanger
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Anel
authors.initials: A
authors.lastname: Tankovic
authors.affiliation: Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Margaret
authors.initials: M
authors.lastname: Au
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Marianne
authors.initials: M
authors.lastname: McGuire
authors.affiliation: Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Michele
authors.initials: M
authors.lastname: Tagliati
authors.affiliation: Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Graham
authors.affiliation: Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Suneeta
authors.initials: S
authors.lastname: Madan-Khetarpal
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, GA, USA.|Center for Functional Evaluation of Rare Variants, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Traynelis
authors.affiliation: Department of Pharmacology, Emory University School of Medicine, Atlanta, GA, USA.|Center for Functional Evaluation of Rare Variants, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Hongjie
authors.initials: H
authors.lastname: Yuan
authors.affiliation: Department of Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA, USA.|Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.|Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Tyler Mark
authors.initials: TM
authors.lastname: Pierson
mesh_terms: D000328:Adult; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism; D002648:Child; D005260:Female; D005998:Glycine / Q000235:genetics; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000473:pathology; D008297:Male; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D021381:Protein Transport / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics*; D011994:Recombinant Proteins / Q000235:genetics
chemical_list: C485668:GRIN1 protein, human; C121001:NR2B NMDA receptor; D009419:Nerve Tissue Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins; D005998:Glycine