Clinical and therapeutic significance of genetic variation in the GRIN gene family encoding NMDARs

• Type of Material: Article
• Authors: Tim A Benke, University of Colorado; Kristen Park, University of Colorado; Ilona Krey, Leipzig Medical Center; Chad R Camp, Emory University; Rui Song, Emory University; Amy J Ramsey, University of Toronto; Hongjie Yuan, Emory University; Stephen Traynelis, Emory University; Johannes Lemke, Leipzig Medical Center
• Language: English
• Date: 2021-10-05
• Publisher: PERGAMON-ELSEVIER SCIENCE LTD
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2021 Elsevier Ltd. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1016/j.neuropharm.2021.108805
• Title of Journal or Parent Work: NEUROPHARMACOLOGY
• Volume: 199
• Start Page: 108805
• End Page: 108805
• Keywords: Intellectual disability; SUBUNIT; ENCEPHALOPATHY; NMDARs; Science & Technology; DIAGNOSIS; Life Sciences & Biomedicine; Neurosciences; RARE VARIANTS; Neurosciences & Neurology; POINT MUTATIONS; MICE LACKING; INTELLECTUAL DISABILITY; Pharmacology & Pharmacy; RECEPTOR GLYCINE AFFINITY; TARGETED DISRUPTION; Epilepsy; FUNCTIONAL CONSEQUENCES; GRIN

Abstract

Considerable genetic variation of N-methyl-D-aspartate receptors (NMDARs) has recently become apparent, with many hundreds of de novo variants identified through widely available clinical genetic testing. Individuals with GRIN variants present with neurological conditions such as epilepsy, autism, intellectual disability (ID), movement disorders, schizophrenia and behavioral disorders. Determination of the functional consequence of genetic variation for NMDARs should lead to precision therapeutics. Furthermore, genetic animal models harboring human variants have the potential to reveal mechanisms that are shared among different neurological conditions, providing strategies that may allow treatment of individuals who are refractory to therapy. Preclinical studies in animal models and small open label trials in humans support this idea. However, additional functional data for variants and animal models corresponding to multiple individuals with the same genotype are needed to validate this approach and to lead to thoughtfully designed, randomized, placebo-controlled clinical trials, which could provide data in order to determine safety and efficacy of potential precision therapeutics.