Functional Analysis of a De Novo Missense GRIN1 Mutation Associated with Intractable Seizures Open Access

Karamchandani, Manish Mahesh (2015)

Permanent URL: https://etd.library.emory.edu/concern/etds/gx41mh98g?locale=en
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Abstract

NMDA receptors (NMDARs) are a subset of ligand gated ion channel glutamate receptors highly involved in normal neuronal function. Dysfunction of NMDARs has been associated with many neurological disorders such as epilepsy, schizophrenia, and developmental delay. In this paper we characterize the effect of a de novo missense mutation in the gene encoding the GluN1 subunit (GRIN1) on NMDAR function and regulation. This mutation (GluN1-A652T) was identified in a 7-year-old patient suffering from medically refractory epilepsy and severe epileptic encephalopathy. The amino acid residue affected by the mutation is located in transmembrane domain 3 (M3), a region of the receptor critical for channel gating. Using electrophysiological recordings, we have determined that the mutation increases potency for the agonists glutamate and glycine when co-expressed with GluN2B, -2C, and -2D. These data suggest that the GluN1-A652T mutation may cause hyper-excitation of neurons through NMDAR overactivity, and thus the patient's epileptic condition. This characterization presents the opportunity for pharmacological rescue through the off label use of FDA-approved NMDAR antagonists. Four FDA-approved compounds were evaluated for their ability to inhibit the GluN1-A652T containing NMDAR as a possible therapy for the patient's phenotype.

Table of Contents

Table of Contents Introduction...1 Methods and Materials...16 Results...19 Discussion...29

References...34

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