title: Functional analysis of a de novo GRIN2A missense mutation associated with early-onset epileptic encephalopathy.
abstract: NMDA receptors (NMDARs), ligand-gated ion channels, play important roles in various neurological disorders, including epilepsy. Here we show the functional analysis of a de novo missense mutation (L812M) in a gene encoding NMDAR subunit GluN2A (GRIN2A). The mutation, identified in a patient with early-onset epileptic encephalopathy and profound developmental delay, is located in the linker region between the ligand-binding and transmembrane domains. Electrophysiological recordings revealed that the mutation enhances agonist potency, decreases sensitivity to negative modulators including magnesium, protons and zinc, prolongs the synaptic response time course and increases single-channel open probability. The functional changes of this amino acid apply to all other NMDAR subunits, suggesting an important role of this residue on the function of NMDARs. Taken together, these data suggest that the L812M mutation causes overactivation of NMDARs and drives neuronal hyperexcitability. We hypothesize that this mechanism underlies the patient's epileptic phenotype as well as cerebral atrophy.
authors: Department of Pharmacology, Emory University School of Medicine, Rollins Research Center, Atlanta, Georgia 30322, USA.
authors: Hongjie
authors: H
authors: Yuan
authors: Department of Pharmacology, Emory University School of Medicine, Rollins Research Center, Atlanta, Georgia 30322, USA.
authors: Kasper B
authors: KB
authors: Hansen
authors: Department of Pharmacology, Emory University School of Medicine, Rollins Research Center, Atlanta, Georgia 30322, USA.
authors: Jing
authors: J
authors: Zhang
authors: 1] Departments of Pediatrics and Neurology, and the Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA [2] NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, and National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors: Tyler Mark
authors: TM
authors: Pierson
authors: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, and National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors: Thomas C
authors: TC
authors: Markello
authors: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, and National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors: Karin V Fuentes
authors: KV
authors: Fajardo
authors: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, and National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors: Conisha M
authors: CM
authors: Holloman
authors: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, and National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors: Gretchen
authors: G
authors: Golas
authors: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, and National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors: David R
authors: DR
authors: Adams
authors: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, and National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors: Cornelius F
authors: CF
authors: Boerkoel
authors: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, and National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors: William A
authors: WA
authors: Gahl
authors: Department of Pharmacology, Emory University School of Medicine, Rollins Research Center, Atlanta, Georgia 30322, USA.
authors: Stephen F
authors: SF
authors: Traynelis
mesh_terms: D000494:Allosteric Regulation; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D002648:Child; D004252:DNA Mutational Analysis; D006801:Humans; D007223:Infant; D008274:Magnesium / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D013036:Spasms, Infantile / Q000235:genetics*; D013329:Structure-Activity Relationship
chemical_list: D008274:Magnesium; D016194:Receptors, N-Methyl-D-Aspartate