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GRIN and Bear the Diverse Functional Effects of Rare NMDA Receptor Variants

Commentary In recent years, significant advances in human genome sequencing and computational analysis of sequencing data have yielded a discovery boom for genetic variants that cause epilepsy (1–3). The identification of these causative genes holds great promise for improving our understanding of epilepsy and how to treat it (4), but there are currently significant barriers between the identification of variants and the application of this knowledge, including creating suitable animal models and model systems in which to interrogate the altered functions of these genes, their protein products, and the networks in which they operate. From a genetic standpoint, this discovery boom has also taught us that there are many ways to make a brain epileptic. Although the standards for calling a gene or a particular variant causative can vary, there are well over 100 genes that have been called such, and within each gene, there can be hundreds of genetic variants that are causative, each of which can affect the expression of the gene or function of the protein in unique ways. This staggering number of potential variants raises a fundamental question when it comes to both mechanistic understanding and treatment design: Do we need to consider each gene variant as a separate case, or do their effects converge at common pathological mechanisms? If the former is true, then there could be a long road ahead, especially if we need to create animal models for each variant. In a recent article, Swanger et al. approached these issues by focusing on genetic variants found in GRIN2A and GRIN2B, both of which are members of the GRIN family of ligand-gated ion channels that code for the NMDA receptor subunits GluN2A and GluN2B, respectively. These variants were missense mutations, meaning that a single nucleotide was changed that switched one amino acid in the protein, and were considered to be pathogenic. The majority of the variants were associated with epilepsy, especially the GRIN2A variants, but some of the GRIN2B variants were associated with intellectual disability. NMDA receptors are well-characterized proteins (5). Extensive structure-function experiments, in combination with crystal structures of the ligand-binding domains and well-defined electrophysiological assays, have led to a good understanding of how different parts of these proteins bind Mechanistic Insight into NMDA Receptor Dysregulation by Rare Variants in the GluN2A and GluN2B Agonist Binding Domains.