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Author Notes:

Correspondence and requests for materials should be addressed to: H.Y. (Email: hyuan@emory.edu)

HY: designed and performed experiments, analyzed data and wrote the paper. KBH: performed experiments and wrote the paper. JZ: performed experiments. TMP: clinical evaluation, patient phenotyping and wrote the paper. TM: supervised genomic data mining. KFF: discovered mutation. CMH: validated mutation. GG: clinical evaluation and patient phenotyping.

DRA: clinical evaluation and patient phenotyping. CFB: project supervision and wrote the paper. WAG: managed UDP and wrote the paper. SFT: designed experiments, analyzed data and wrote the paper. All authors discussed the results and implications and commented on the manuscript.

We are grateful to Anel Tankovic, Phuong Le, and Kevin Ogden for technical assistance. We are also grateful to Eric D. Marsh and Dimitre R. Simeonov for assistance with the clinical and molecular evaluation of the patient.

The authors have no competing interests.

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Research Funding:

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
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • MULTIDISCIPLINARY SCIENCES
  • D-ASPARTATE RECEPTOR
  • VOLTAGE-DEPENDENT BLOCK
  • NMDA RECEPTOR
  • STRUCTURAL DETERMINANTS
  • ENDOPLASMIC-RETICULUM
  • EXTRACELLULAR VESTIBULE
  • TRANSMEMBRANE PROTEINS
  • IDIOPATHIC EPILEPSIES
  • GLUTAMATE RECEPTORS
  • SPECTRUM DISORDERS

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

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Journal Title:

Nature Communications

Volume:

Volume 5

Publisher:

, Pages 3251-3251

Type of Work:

Article | Final Publisher PDF

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.

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