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Author Notes:

Current Address: Department of Neurology, Shanxi Medical University First Hospital, Taiyuan, China E-mailL hyuan@emory.edu; Email:jiangyuwu@bjmu.edu.cn

Author Contributions: Conceptualization: SFT HY YJ; Data curation: SFT HY YJ; Formal analysis: KG SFT HY YJ. Funding acquisition: SFT HY YJ; Investigation: KG AT YZ HK JZ WC WX GHS CH HY; Methodology: SFT HY YJ; Project administration: SFT HY YJ; Resources: SFT HY YJ; Supervision: SFT HY YJ; Validation: KG SFT HY YJ; Visualization: KG HY; Writing – original draft: KG AT YZ WC WX CH SFT HY YJ; Writing – review & editing: KG HK JZ GHS SFT HY YJ

We thank Jing Zhang for outstanding technical assistance, and Riley Perszyk, and Dr. Feng Yi for critical assistance with experiments and analysis.

S.F.T. is a paid consultant for Janssen Pharmaceuticals, NeurOp, Inc., and Pfizer Inc, and co-founder of NeurOp Inc.

This does not alter our adherence to PLOS ONE policies on sharing data and materials.


Research Funding:

This work was supported by the Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) of the National Institutes of Health (NIH) under award number R01HD082373 to H.Y., by the National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health (NIH) under award number R01NS036654, R01NS065371, R24NS092989 to S.F.T., by the Xiangya-Emory Medical Schools Visiting Student Program to W.C.; by the National Basic Research Program of China (973 program, grant number: 2012CB944600), by the National Natural Science Foundation of China (grant number: 81271439), by the Beijing Natural Science Foundation (grant number: 7151010), by the Beijing Municipal Science & Technology Commission (grant number: Z161100000216133), by the Beijing Institute for Brain Disorders Foundation (grant number: BIBDPXM2014_014226_000016) and the Beijing Municipal Natural Science Key Project (grant number: 15G10050).

The content is solely the responsibility of the authors and does not necessarily represent the official views of the funding agencies.

Adenovo loss-of-function GRIN2A mutation associated with childhood focal epilepsy and acquired epileptic aphasia

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Journal Title:



Volume 12, Number 2


, Pages e0170818-e0170818

Type of Work:

Article | Final Publisher PDF


Objective: N-methyl-D-aspartate receptors (NMDAR) subunit GRIN2A/GluN2A mutations have been identified in patients with Objective N-methyl-D-aspartate receptors (NMDAR) subunit GRIN2A/GluN2A mutations have been identified in patients with various neurological diseases, such as epilepsy and intellectual disability / developmental delay (ID/DD). In this study, we investigated the phenotype and underlying molecular mechanism of a GRIN2A missense mutation identified by next generation sequencing on idiopathic focal epilepsy using in vitro electrophysiology. Methods Genomic DNA of patients with epilepsy and ID/DD were sequenced by targeted next-generation sequencing within 300 genes related to epilepsy and ID/DD. The effects of one missense GRIN2A mutation on NMDAR function were evaluated by two-electrode voltage clamp current recordings and whole cell voltage clamp current recordings. Results We identified one de novo missense GRIN2A mutation (Asp731Asn, GluN2A(D731N)) in a child with unexplained epilepsy and DD. The D731N mutation is located in a portion of the agonist-binding domain (ABD) in the GluN2A subunit, which is the binding pocket for agonist glutamate. This residue in the ABD is conserved among vertebrate species and all other NMDAR subunits, suggesting an important role in receptor function. The proband shows developmental delay as well as EEG-confirmed seizure activity. Functional analyses reveal that the GluN2A(D731N) mutation decreases glutamate potency by over 3,000-fold, reduces amplitude of current response, shortens synaptic-like response time course, and decreases channel open probability, while enhancing sensitivity to negative allosteric modulators, including extracellular proton and zinc inhibition. The combined effects reduce NMDAR function. Significance We identified a de novo missense mutation in the GRIN2A gene in a patient with childhood focal epilepsy and acquired epileptic aphasia. The mutant decreases NMDAR activation suggesting NMDAR hypofunction may contribute to the epilepsy pathogenesis.

Copyright information:

© 2017 Gao et al

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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