Heterogeneous clinical and functional features of GRIN2D-related developmental and epileptic encephalopathy.
Adult
Amino Acid Sequence
/ genetics
Animals
Child
Child, Preschool
Epilepsy, Generalized
/ genetics
Female
Gene Expression Regulation
/ genetics
Glutamic Acid
/ metabolism
HEK293 Cells
Humans
Male
Neurons
/ metabolism
Polymorphism, Single Nucleotide
/ genetics
Rats
Rats, Sprague-Dawley
Receptors, N-Methyl-D-Aspartate
/ genetics
Synaptic Transmission
/ genetics
GluN
NMDA receptor
channelopathy
functional genomics
glutamate receptor
Journal
Brain : a journal of neurology
ISSN: 1460-2156
Titre abrégé: Brain
Pays: England
ID NLM: 0372537
Informations de publication
Date de publication:
01 10 2019
01 10 2019
Historique:
received:
14
01
2019
revised:
30
04
2019
accepted:
31
05
2019
pubmed:
11
9
2019
medline:
17
6
2020
entrez:
11
9
2019
Statut:
ppublish
Résumé
N-methyl d-aspartate receptors are ligand-gated ionotropic receptors mediating a slow, calcium-permeable component of excitatory synaptic transmission in the CNS. Variants in genes encoding NMDAR subunits have been associated with a spectrum of neurodevelopmental disorders. Here we report six novel GRIN2D variants and one previously-described disease-associated GRIN2D variant in two patients with developmental and epileptic encephalopathy. GRIN2D encodes for the GluN2D subunit protein; the GluN2D amino acids affected by the variants in this report are located in the pre-M1 helix, transmembrane domain M3, and the intracellular carboxyl terminal domain. Functional analysis in vitro reveals that all six variants decreased receptor surface expression, which may underline some shared clinical symptoms. In addition the GluN2D(Leu670Phe), (Ala675Thr) and (Ala678Asp) substitutions confer significantly enhanced agonist potency, and/or increased channel open probability, while the GluN2D(Ser573Phe), (Ser1271Phe) and (Arg1313Trp) substitutions result in a mild increase of agonist potency, reduced sensitivity to endogenous protons, and decreased channel open probability. The GluN2D(Ser573Phe), (Ala675Thr), and (Ala678Asp) substitutions significantly decrease current amplitude, consistent with reduced surface expression. The GluN2D(Leu670Phe) variant slows current response deactivation time course and increased charge transfer. GluN2D(Ala678Asp) transfection significantly decreased cell viability of rat cultured cortical neurons. In addition, we evaluated a set of FDA-approved NMDAR channel blockers to rescue functional changes of mutant receptors. This work suggests the complexity of the pathological mechanisms of GRIN2D-mediated developmental and epileptic encephalopathy, as well as the potential benefit of precision medicine.
Identifiants
pubmed: 31504254
pii: 5557839
doi: 10.1093/brain/awz232
pmc: PMC6763743
doi:
Substances chimiques
GRIN2D protein, human
0
NR2D NMDA receptor
0
Receptors, N-Methyl-D-Aspartate
0
Glutamic Acid
3KX376GY7L
Types de publication
Case Reports
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3009-3027Subventions
Organisme : NINDS NIH HHS
ID : R01 NS065371
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS043277
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS036654
Pays : United States
Organisme : NICHD NIH HHS
ID : R01 HD082373
Pays : United States
Organisme : NINDS NIH HHS
ID : R24 NS092989
Pays : United States
Organisme : NINDS NIH HHS
ID : R35 NS111619
Pays : United States
Informations de copyright
© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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