Recurrent seizure-related GRIN1 variant: Molecular mechanism and targeted therapy.
Ann Clin Transl Neurol
; 8(7): 1480-1494, 2021 07.
Article
en En
| MEDLINE
| ID: mdl-34227748
ABSTRACT
OBJECTIVE:
Genetic variants in the GRIN genes that encode N-methyl-D-aspartate receptor (NMDAR) subunits have been identified in various neurodevelopmental disorders, including epilepsy. We identified a GRIN1 variant from an individual with early-onset epileptic encephalopathy, evaluated functional changes to NMDAR properties caused by the variant, and screened FDA-approved therapeutic compounds as potential treatments for the patient.METHODS:
Whole exome sequencing identified a missense variant in GRIN1. Electrophysiological recordings were made from Xenopus oocytes and transfected HEK cells to determine the NMDAR biophysical properties as well as the sensitivity to agonists and FDA-approved drugs that inhibit NMDARs. A beta-lactamase reporter assay in transfected HEK cells evaluated the effects of the variant on the NMDAR surface expression.RESULTS:
A recurrent de novo missense variant in GRIN1 (c.1923G>A, p.Met641Ile), which encodes the GluN1 subunit, was identified in a pediatric patient with drug-resistant seizures and early-onset epileptic encephalopathy. In vitro analysis indicates that GluN1-M641I containing NMDARs showed enhanced agonist potency and reduced Mg2+ block, which may be associated with the patient's phenotype. Results from screening FDA-approved drugs suggested that GluN1-M641I containing NMDARs are more sensitive to the NMDAR channel blockers memantine, ketamine, and dextromethorphan compared to the wild-type receptors. The addition of memantine to the seizure treatment regimen significantly reduced the patient's seizure burden.INTERPRETATION:
Our finding contributes to the understanding of the phenotype-genotype correlations of patients with GRIN1 gene variants, provides a molecular mechanism underlying the actions of this variant, and explores therapeutic strategies for treating GRIN1-related neurological conditions.
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Convulsiones
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Variación Genética
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Receptores de N-Metil-D-Aspartato
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Mutación Missense
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Secuenciación del Exoma
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Proteínas del Tejido Nervioso
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Ann Clin Transl Neurol
Año:
2021
Tipo del documento:
Article