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

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.

Automated summary

Recent discoveries have shown a significant genetic variation in NMDARs, with individuals carrying GRIN variants presenting with various neurological conditions. Understanding the functional consequences of these genetic variations could lead to precision therapeutics. Animal models with human variants may uncover shared mechanisms among different neurological conditions, requiring further research and clinical trials to validate and determine the effectiveness of treatment methods.