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A novel missense mutation in GRIN2A causes a nonepileptic neurodevelopmental disorder
Author(s) -
FernándezMarmiesse Ana,
Kusumoto Hirofumi,
Rekarte Saray,
Roca Iria,
Zhang Jin,
Myers Scott J.,
Traynelis Stephen F.,
Couce Mª Luz,
GutierrezSolana Luis,
Yuan Hongjie
Publication year - 2018
Publication title -
movement disorders
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.352
H-Index - 198
eISSN - 1531-8257
pISSN - 0885-3185
DOI - 10.1002/mds.27315
Subject(s) - missense mutation , neurodevelopmental disorder , mutation , epilepsy , glutamate receptor , nmda receptor , medicine , neuroscience , genetics , biology , gene , receptor
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. Conclusion: De novo GRIN2A mutations can give rise to a neurodevelopmental and movement disorder without epilepsy. © 2018 International Parkinson and Movement Disorder Society