The p.Glu787Lys variant in the GRIA3 gene causes developmental and epileptic encephalopathy mimicking structural epilepsy in a female patient.

ABSTRACT

The GRIA3 gene is located in the X chromosome and encodes for one of the subunits (iGluR3) of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), an excitatory synaptic transmission receptor present in most parts of the brain. iGluR3 dysfunction has been associated with both abnormal memory formation and learning. It has been observed in patients with different neurological and cognitive disorders, including epilepsy. Three different de novo missense variants of GRIA3 have recently been reported in patients with Developmental and Epileptic Encephalopathy (DEE). We report on a female pediatric patient with DEE whose clinical picture mimicked structural epilepsy. We give a detailed description of our patient's most important electro-clinical features. Genetic analysis revealed that the patient carried a de novo missense variant in GRIA3 (c.2359G>A; p.Glu787Lys). The p.Glu787Lys variant had previously been reported in a male pediatric patient. Additionally, we studied iGluR3 expression in the patient and control fibroblasts. We found significantly lower iGluR3 expression in the patient's fibroblasts than in controls and different responses to glutamate treatment. In summary, our report expands knowledge of GRIA3 variants affecting boys and girls, describes functional studies of these variants, and provides an extensive review of the literature concerning GRIA3 genetic variants.