A Novel Missense Mutation in GRIN2A Causes a Nonepileptic Neurodevelopmental Disorder

Overview

Journal Mov Disord

Date 2018 Apr 13

PMID 29644724

Citations 21

Authors

Ana Fernandez-Marmiesse

Hirofumi Kusumoto

Saray Rekarte

Iria Roca

Jin Zhang

Scott J Myers

Stephen F Traynelis

MA Luz Couce

Luis Gutierrez-Solana

Hongjie Yuan

Affiliations

Soon will be listed here.

Abstract

Background: Mutations in the GRIN2A gene, which encodes the GluN2A (glutamate [NMDA] receptor subunit epsilon-1) subunit of the N-methyl-d-aspartate receptor, have been identified in patients with epilepsy-aphasia spectrum disorders, idiopathic focal epilepsies with centrotemporal spikes, and epileptic encephalopathies with severe developmental delay. However, thus far, mutations in this gene have not been associated with a nonepileptic neurodevelopmental disorder with dystonia.

Objectives: The objective of this study was to identify the disease-causing gene in 2 siblings with neurodevelopmental and movement disorders with no epileptiform abnormalities.

Methods: The study method was targeted next-generation sequencing panel for neuropediatric disorders and subsequent electrophysiological studies.

Results: The 2 siblings carry a novel missense mutation in the GRIN2A gene (p.Ala643Asp) that was not detected in genomic DNA isolated from blood cells of their parents, suggesting that the mutation is the consequence of germinal mosaicism in 1 progenitor. In functional studies, the GluN2A-A643D mutation increased the potency of the agonists L-glutamate and glycine and decreased the potency of endogenous negative modulators, including protons, magnesium and zinc but reduced agonist-evoked peak current response in mammalian cells, suggesting that this mutation has a mixed effect on N-methyl-d-aspartate receptor function.

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