AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders
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Salpietro, Vincenzo | Dixon, Christine | Guo, Hui | Bello, Oscar | Vandrovcova, Jana, J | Efthymiou, Stephanie | Maroofian, Reza | Heimer, Gali | Burglen, Lydie | Valence, Stephanie | Torti, Erin | Hacke, Moritz | Rankin, Julia | Tariq, Huma | Colin, Estelle | Procaccio, Vincent | Striano, Pasquale | Mankad, Kshitij | Lieb, Andreas | Chen, Sharon | Pisani, Laura | Bettencourt, Conceição | Männikkö, Roope | Manole, Andreea | Brusco, Alfredo | Grosso, Enrico, Del | Ferrero, Giovanni Battista | Armstrong-Moron, Judith | Gueden, Sophie | Bar-Yosef, Omer | Tzadok, Michal | Monaghan, Kristin | Santiago-Sim, Teresa | Person, Richard, E. | Cho, Megan, T | Willaert, Rebecca | Yoo, Yongjin | Chae, Jong-Hee | Quan, Yingting | Wu, Huidan | Wang, Tianyun | Bernier, Raphael | Xia, Kun | Blesson, Alyssa | Jain, Mahim | Motazacker, Mohammad | Jaeger, Bregje | Schneider, Amy | Boysen, Katja | Muir, Alison | Myers, Candace | Gavrilova, Ralitza | Gunderson, Lauren | Schultz-Rogers, Laura | Klee, Eric | Dyment, David | Osmond, Matthew, M | Parellada, Mara | Llorente, Cloe | Gonzalez-Peñas, Javier | Carracedo, Angel | van Haeringen, Arie | Ruivenkamp, Claudia | Nava, Caroline | Héron, Delphine | Nardello, Rosaria | Iacomino, Michele | Minetti, Carlo | Skabar, Aldo | Fabretto, Antonella | Raspall-Chaure, Miquel | Chez, Michael | Tsai, Anne | Fassi, Emily | Shinawi, Marwan | Constantino, John, N. | de Zorzi, Rita | Fortuna, Sara | Kok, Fernando | Keren, Boris | Bonneau, Dominique | Choi, Murim | Benzeev, Bruria | Zara, Federico | Mefford, Heather | Scheffer, Ingrid, E. | Clayton-Smith, Jill | Macaya, Alfons | Rothman, James, E | Eichler, Evan | Kullmann, Dimitri | Houlden, Henry | Dauvilliers, Yves
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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 post-transcriptional editing at the Q607 site, it renders heteromultimeric AMPARs Ca2+-impermeable, with a linear relationship between current and trans-membrane 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 co-expressed 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.
