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

Hongjie Yuan (), Kasper B. Hansen, Jing Zhang, Tyler Mark Pierson, Thomas C. Markello, Karin V. Fuentes Fajardo, Conisha M. Holloman, Gretchen Golas, David R. Adams, Cornelius F. Boerkoel, William A. Gahl and Stephen F. Traynelis
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Hongjie Yuan: Emory University School of Medicine, Rollins Research Center
Kasper B. Hansen: Emory University School of Medicine, Rollins Research Center
Jing Zhang: Emory University School of Medicine, Rollins Research Center
Tyler Mark Pierson: and the Regenerative Medicine Institute, Cedars-Sinai Medical Center
Thomas C. Markello: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, and National Human Genome Research Institute, National Institutes of Health
Karin V. Fuentes Fajardo: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, and National Human Genome Research Institute, National Institutes of Health
Conisha M. Holloman: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, and National Human Genome Research Institute, National Institutes of Health
Gretchen Golas: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, and National Human Genome Research Institute, National Institutes of Health
David R. Adams: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, and National Human Genome Research Institute, National Institutes of Health
Cornelius F. Boerkoel: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, and National Human Genome Research Institute, National Institutes of Health
William A. Gahl: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, National Institutes of Health, and National Human Genome Research Institute, National Institutes of Health
Stephen F. Traynelis: Emory University School of Medicine, Rollins Research Center

Nature Communications, 2014, vol. 5, issue 1, 1-12

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms4251

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