Abstract
Background: The N-methyl-D-aspartate receptor (NMDAR) is an ionotropic glutamate receptor that has important roles in synaptogenesis, synaptic transmission, and synaptic plasticity. Recently, a large number of rare genetic variants have been found in NMDAR subunits in people with neurodevelopmental disorders, and also in healthy individuals. One such is the GluN2AR586K variant, found in a person with intellectual disability. Identifying the functional consequences, if any, of such variants allows their potential contribution to pathogenesis to be assessed. Here, we assessed the effect of the GluN2AR586K variant on NMDAR pore properties. Methods: We expressed recombinant NMDARs with and without the GluN2AR586K variant in Xenopus laevis oocytes and in primary cultured mouse neurons, and made electrophysiological recordings assessing Mg2+ block, single-channel conductance, mean open time and current density. Results: The GluN2AR586K variant was not found to influence any of the properties assessed. Conclusions: Our findings suggest it is unlikely that the GluN2AR586K variant contributes to the pathogenesis of neurodevelopmental disorder.
Highlights
We have added further information on GRIN2A genetic variation in neurodevelopmental disorders, we have kept this brief as our aim is not to review the area
The GluN2AR586K mutation has no effect on Mg2+ block or current density We first expressed GluN2AWT and GluN2AR586K–containing N-methyl-D-aspartate receptor (NMDAR) in X. laevis oocytes and made two-electrode voltage clamp recordings of block by Mg2+ of glutamate-evoked currents
In the present study, we investigated the functional consequences of a GluN2A point variation found previously in a person with epilepsy/EEG abnormalities and intellectual disability
Summary
We have added further information on GRIN2A genetic variation in neurodevelopmental disorders, we have kept this brief as our aim is not to review the area. It would be useful to have more of an overview of how genetic variation within GRIN2A is thought to contribute to brain disease, i.e. genotype-phenotype relationships (e.g. type of mutations, mode of inheritance, ‘causative’ for disease or associated with increased risk of disease) It should be stated in the introduction that in silico tools had been used to predict the function consequence of this variant (as presented by Endele et al, 2010, supplementary Table 2) and that such prediction tools including others not used by Endele et al, indicate that this variant is predicted to be consistently ‘possibly damaging’ as opposed to benign. Conclusions: Our findings suggest it is unlikely that the GluN2AR586K variant contributes to the pathogenesis of neurodevelopmental disorder
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