Functional analysis of a de novo GRIN2A missense mutation associated with early-onset epileptic encephalopathy

• Type of Material: Article
• Authors: Hongjie Yuan, Emory University; Kasper B. Hansen, Emory University; Jing Zhang, Emory University; Tyler Mark Pierson, Cedars-Sinai Medical Center; Thomas C. Markello, National Institutes of Health; Karin V. Fuentes Fajardo, National Institutes of Health; Conisha M. Holloman, National Institutes of Health; Gretchen Golas, National Institutes of Health; David R. Adams, National Institutes of Health; Cornelius F. Boerkoel, National Institutes of Health; William A. Gahl, National Institutes of Health; Stephen Traynelis, Emory University
• Language: English
• Date: 2014-02-01
• Publisher: Nature Publishing Group: Nature Communications
• Publication Version: Final Published Version
• Copyright Statement: © 2014, Rights Managed by Nature Publishing Group. Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use.
• Final Published Version (URL): http://dx.doi.org/10.1038/ncomms4251
• Title of Journal or Parent Work: Nature Communications
• ISSN: 2041-1723
• Volume: 5
• Start Page: 3251
• End Page: 3251
• Grant/Funding Information: This work was supported by the NINDS (NS036654, S.F.T.), by the NIH Undiagnosed Disease Program (HSN268201300162P, H.Y.), and by the Intramural Research Program of the National Human Genome Research Institute. TMP was also supported by the Cedars-Sinai Diana and Steve Marienhoff Fashion Industries Guild Endowed Fellowship in Pediatric Neuromuscular Diseases.
• Keywords: Science & Technology - Other Topics; MULTIDISCIPLINARY SCIENCES; VOLTAGE-DEPENDENT BLOCK; Multidisciplinary Sciences; SPECTRUM DISORDERS; Science & Technology; STRUCTURAL DETERMINANTS; TRANSMEMBRANE PROTEINS; ENDOPLASMIC-RETICULUM; NMDA RECEPTOR; D-ASPARTATE RECEPTOR; IDIOPATHIC EPILEPSIES; EXTRACELLULAR VESTIBULE; GLUTAMATE RECEPTORS
• Research Categories: Health Sciences, Health Care Management; Health Sciences, Pharmacy

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.