A novel NMDA-receptor mutation in a neurologic disorder

Since 2010, a large repertoire of de novo mutations (~150) has been found within the N-methyl-D-aspartate receptor (NMDAR) gene-family; linking the receptors to a variety of neurodevelopmental disorders, intellectual disabilities, autism, epilepsy and schizophrenia. However, how precise mutations translate to brain disorders remains unknown. Here, we describe a de novo heterozygous GRIN2B mutation discovered by whole exome sequencing (WES) in a pediatric proband with severe developmental delays and intellectual disability. Electrophysiological recording and pharmacological profiling show that the mutation reduces the receptor’s affinity towards glutamate by ~1000-fold; the largest shift ever described for this receptor to date. The mutation has no effect on the receptor’s glycine affinity, with a very mild, albeit noticeable, loss in affinity towards magnesium; a potent native channel blocker found in CNS. We also find a single mention in the literature of another mutation of this residue (i.e., substitution to another amino acid), however without characterization. Notably, the probands display several common indications, such as developmental delays and mental disability, but differ in others such as seizures noted solely in the second patient. We generated this mutation and find it to engender an even more extreme loss of function of the receptor towards glutamate. How, then, does the severe loss-of-function of this receptor leads to two different disease phenotypes? We are now in the process of following-up on these mechanisms with the use of novel transgenic mouse models, generation of stable cell lines for high throughput drug-screening, not to mention employing unique optogenetic tools to silence or activate NMDARs in neurons.