A de novo loss-of-function GRIN2A mutation associated with childhood focal epilepsy and acquired epileptic aphasia

• DOI: 10.1371/journal.pone.0170818
• Publication Date: 2017-02-09T19:06:34Z
• Authors: Kai Gao; Anel Tankovic; Yujia Zhang; Hirofumi Kusumoto; Jin Zhang; Wenjuan Chen; Wenshu XiangWei; Gil H. Shaulsky; Chun Hu; Stephen F. Traynelis; Hongjie Yuan; Yuwu Jiang
• Keywords: Male; 0301 basic medicine; Landau-Kleffner Syndrome; Science; Q; R; Mutation, Missense; High-Throughput Nucleotide Sequencing; Electroencephalography; Receptors, N-Methyl-D-Aspartate; Membrane Potentials; 3. Good health; 03 medical and health sciences; HEK293 Cells; Amino Acid Substitution; Medicine; Humans; Female; Epilepsies, Partial; Research Article

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