LAUSR

AMPA Receptor GluA2 Subunit Defects Are a Cause of Neurodevelopmental Disorders Salpietro V, Dixon CL, Guo H, et al. Nat Commun. 2019;10:3094. doi:10.1038/s41467-019-10910-w 4-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid (AMPA) receptors (AMPARs) are tetrameric ligand–gated channels made up of combinations of GluA1-4 subunits encoded by GRIA1-4 genes. GluA2 has an especially important role because, following posttranscriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca2+-impermeable, with a linear relationship between current and transmembrane voltage. Here, we report heterozygous de novo GRIA2 mutations in 28 unrelated patients with intellectual disability (ID) and neurodevelopmental abnormalities, including autism spectrum disorder (ASD), Rett syndrome-like features, and seizures or developmental epileptic encephalopathy (DEE). In functional expression studies, mutations lead to a decrease in agonist-evoked current mediated by mutant subunits compared to wild-type channels. When GluA2 subunits are coexpressed with GluA1, most GRIA2 mutations cause a decreased current amplitude, and some also affect voltage rectification. Our results show that de novo variants in GRIA2 can cause neurodevelopmental disorders, complementing evidence that other genetic causes of ID, ASD, and DEE also disrupt glutamatergic synaptic transmission.