GRIN2A-related disorders: genotypes, functional consequences, and phenotypes
N-methyl-D-aspartate receptor (NMDARs) are glutamate-gated ion channels with broad distribution in the brain. They are involved in neurodevelopment, neuronal plasticity and memory formation, and are members of the ionotropic glutamate receptor (iGluR) superfamily that contribute a slow, Ca2+ permeable component of the excitatory synaptic current. Aberrant ion channel functions in these receptors therefore often result in psychiatric or neurological disorders. Numerous inherited or de novo variations in the genes encoding NMDAR subunits (GRIN gene family) have been identified in patients with neuropsychiatric disorders thanks to the next-generation sequencing techniques. However, the majority of these variants remain unexplored and occur at sites in the protein with unidentified function or alter receptor properties in unanticipated ways. Alterations of the NMDAR subunit GluN2A, encoded by GRIN2A, have been especially associated with epilepsy-aphasia spectrum, which is a spectrum of disorders identified in children with epilepsy, prominent speech-related features, developmental delay (DD), intellectual disability (ID) and mental retardation. Although the large amount of sequencing information is growing, there is virtually limited functional analysis available to determine how the mutations impact the receptor function or clinical phenotype, which blunts ability to render diagnosis or craft novel treatments tailored to the patient. The program is to analyze human standing variations in GRIN2A by molecular and electrophysiological ways to illustrate the landscape of genetic variation intolerance among distinct domains within the GRIN genes. Also, this program aims at elucidating genetic and functional correlates, as well as delineating the wide phenotypic profile of GRIN2A-related spectrum disorders.