AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

Authors: Vincenzo Salpietro, Christine L. Dixon, Hui Guo, Oscar D. Bello, Jana Vandrovcová, Stéphanie Efthymiou, Reza Maroofian, Gali Heimer, Lydie Bürglen, Stéphanie Valence, Erin Torti, Moritz Hacke, Julia Rankin, Huma Tariq, Estelle Colin, Vincent Procaccio, Pasquale Striano, Kshitij Mankad, Andreas Lieb, Sharon Chen, Laura Rosa Pisani, Conceição Bettencourt, Roope Männikkö, Andreea Manole, Alfredo Brusco, Enrico Grosso, Giovanni Battista Ferrero, Judith Armstrong-Moron, Sophie Guéden, Omer Bar‐Yosef, Michal Tzadok, Kristin G. Monaghan, Teresa Santiago‐Sim, Richard Person, Megan T. Cho, Rebecca Willaert, Yongjin Yoo, Jong‐Hee Chae, Yingting Quan, Huidan Wu, Tianyun Wang, Raphael Bernier, Kun Xia, Alyssa Blesson, Mahim Jain, Mohammad Mahdi Motazacker, Bregje Jaeger, Amy Schneider, Katja Boysen, Alison M. Muir, Candace T. Myers, Ralitza H. Gavrilova, Lauren Gunderson, Laura Schultz‐Rogers, Eric W. Klee, David A. Dyment, Matthew Osmond, Mara Parellada, Cloe Llorente, Javier González‐Peñas, Ángel Carracedo, Arie van Haeringen, Claudia Ruivenkamp, Caroline Nava, Delphine Héron, Rosaria Nardello, Michele Iacomino, Carlo Minetti, Aldo Skabar, Antonella Fabretto, SYNAPS Study Group, Michael G. Hanna, Enrico Bugiardini, Isabel C. Hostettler, Benjamin O’Callaghan, Alaa Khan, Andrea Cortese, Emer O’Connor, Wai Y. Yau, Thomas Bourinaris, Rauan Kaiyrzhanov, Viorica Chelban, M Madej, Maria C. Diana, Maria S. Vari, Marina Pedemonte, Claudio Bruno, Ganna Balagura, Marcello Scala, Chiara Fiorillo, Lino Nobili, Nancy T. Malintan, M. Natalia Zanetti, Shyam S. Krishnakumar, Gabriele Lignani, James E.C. Jepson, Paolo Broda, Sımona Baldassari, Pia Rossi, Floriana Fruscione, Francesca Madia, Monica Traverso, Patrizia De Marco, Belén Pérez‐Dueñas, Francina Munell, Yamna Kriouile, Mohamed El-Khorassani, Blagovesta Marinova Karashova, Daniela Avdjieva, Hadil Kathom, Radka Tincheva, Lionel Van-Maldergem, Wolfgang Nachbauer, Sylvia Boesch, Antonella Gagliano, Elisabetta Amadori, Jatinder S. Goraya, Tipu Sultan, Salman Kirmani, Shahnaz Ibrahim, Farida Jan, Jun Mine, Selina Banu, Pierangelo Veggiotti, Gianvincenzo Zuccotti, Michel D. Ferrari, Arn M. J. Van Den Maagdenberg, Alberto Verrottı, Gian Luigi Marseglia, Salvatore Savasta, Miguel A. Soler, Carmela Scuderi, Eugenia Borgione, Roberto Chimenz, Eloisa Gitto, Valeria Dipasquale, Alessia Sallemi, Monica Fusco, Caterina Cuppari, Maria Concetta Cutrupi, Martino Ruggieri, Armando Cama, Valeria Capra, Niccolò E. Mencacci, Richard G. Boles, Neerja Gupta, Madhulika Kabra, Savvas Papacostas, Eleni Zamba‐Papanicolaou, Efthimios Dardiotis, Shazia Maqbool, Nuzhat Rana, Osama Atawneh, Shen‐Yang Lim, Mohd. Farooq Shaikh, George Koutsis, Marianthi Breza, Domenico Coviello, Yves Dauvilliers, Issam Al-Khawaja, Mariam Alkhawaja, Fuad Al-Mutairi, Tanya Stojkovic, Veronica Ferrucci, Massimo Zollo, Fowzan S. Alkuraya, Maria Kinali, Sherifa A. Hamed, Hanène Benrhouma, Ilhem Turki, Mériem Tazir, Makram Obeid, Sophia Bakhtadze, Nebal Waill Saadi, Maha S. Zaki, Chahnez Triki, Fabio Benfenati, Stefano Gustincich, Majdi Kara, Vincenzo Belcastro, Nicola Specchio, Giuseppe Capovilla, Ehsan Ghayoor Karimiani, Ahmed Salih, Njideka Okubadejo, Oluwadamilola O. Ojo, Olajumoke Oshinaike, Olapeju Oguntunde, Kolawole Wahab, Abiodun Bello, Sanni Abubakar, Yahaya Obiabo, Ernest Nwazor, Oluchi Ekenze, Uduak Williams, Alagoma Iyagba, Lolade Taiwo, Morenikeji Komolafe, Konstantin Senkevich, Chingiz Shashkin, Nazira Zharkynbekova, Kairgali Koneyev, Ganieva Manizha, Maksud Isrofilov, Ulviyya Guliyeva, Kamran Salayev, Samson Khachatryan, Salvatore Rossi, Gabriella Silvestri, Nourelhoda A. Haridy, Luca A. Ramenghi, Georgia Xiromerisiou, Emanuele David, M. Aguennouz, Liana Fidani, Cleanthe Spanaki, Arianna Tucci, Miquel Raspall‐Chaure, Michael Chez, Anne Tsai, Emily Fassi, Marwan Shinawi, John N. Constantino, Rita De Zorzi, Sara Fortuna, Fernando Kok, Boris Keren, Dominique Bonneau, Murim Choi, Bruria Ben‐Zeev, Federico Zara, Heather C. Mefford, Ingrid E. Scheffer, Jill Clayton‐Smith, Alfons Macaya, James E. Rothman, Evan E. Eichler, Dimitri M. Kullmann, Henry Houlden - Nature Communications 2019 cited by 249

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 Ca 2+ -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.