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.

AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

Brusco, Alfredo;Ferrero, Giovanni Battista;
2019

Abstract

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.
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https://www.nature.com/articles/s41467-019-10910-w
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6626132/
AMPA receptor, GluA2, neurodevelopmental disorders, autism spectrum disorder, glutamatergic synaptic transmission, GRIA2
Salpietro, Vincenzo; Dixon, Christine L; Guo, Hui; Bello, Oscar D; Vandrovcova, Jana; 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, Conceicao; Männikkö, Roope; Manole, Andreea; Brusco, Alfredo; Grosso, Enrico; Ferrero, Giovanni Battista; Armstrong-Moron, Judith; Gueden, Sophie; Bar-Yosef, Omer; Tzadok, Michal; Monaghan, Kristin G; Santiago-Sim, Teresa; Person, Richard E; Cho, Megan T; Willaert, Rebecca; Yoo, Yongjin; Chae, Jong-Hee; Quan, Yingting; Wu, Huidan; Wang, Tianyun; Bernier, Raphael A; Xia, Kun; Blesson, Alyssa; Jain, Mahim; Motazacker, Mohammad M; Jaeger, Bregje; Schneider, Amy L; Boysen, Katja; Muir, Alison M; Myers, Candace T; Gavrilova, Ralitza H; Gunderson, Lauren; Schultz-Rogers, Laura; Klee, Eric W; Dyment, David; Osmond, Matthew; Parellada, Mara; Llorente, Cloe; Gonzalez-Peñas, Javier; Carracedo, Angel; Van Haeringen, Arie; Ruivenkamp, Claudia; Nava, Caroline; Heron, 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 C; Scheffer, Ingrid E; Clayton-Smith, Jill; Macaya, Alfons; Rothman, James E; Eichler, Evan E; Kullmann, Dimitri M; Houlden, Henry
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2318/1706458
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