AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

Vincenzo Salpietro, Christine L. Dixon, Hui Guo, Oscar D. Bello, Jana Vandrovcova, Stephanie Efthymiou, Reza Maroofian, Gali Heimer, Lydie Burglen, Stephanie Valence, Erin Torti, Moritz Hacke, Julia Rankin, Huma Tariq, Estelle Colin, Vincent Procaccio, Pasquale Striano, Kshitij Mankad, Andreas Lieb, Sharon ChenLaura Pisani, Conceicao Bettencourt, Roope Männikkö, Andreea Manole, Alfredo Brusco, Enrico Grosso, Giovanni Battista Ferrero, Judith Armstrong-Moron, Sophie Gueden, Omer Bar-Yosef, Michal Tzadok, Kristin G. Monaghan, Teresa Santiago-Sim, Richard E. Person, Megan T. Cho, Rebecca Willaert, Yongjin Yoo, Jong Hee Chae, Yingting Quan, Huidan Wu, Tianyun Wang, Raphael A. Bernier, Kun Xia, Alyssa Blesson, Mahim Jain, Mohammad M. Motazacker, Bregje Jaeger, Amy L. Schneider, Katja Boysen, Alison M. Muir, Candace T. Myers, Ralitza H. Gavrilova, Lauren Gunderson, Laura Schultz-Rogers, Eric W. Klee, David Dyment, Matthew Osmond, Mara Parellada, Cloe Llorente, Javier Gonzalez-Peñas, Angel Carracedo, Arie Van Haeringen, Claudia Ruivenkamp, Caroline Nava, Delphine Heron, Rosaria Nardello, Michele Iacomino, Carlo Minetti, Aldo Skabar, Antonella Fabretto, Michael G. Hanna, Enrico Bugiardini, Isabel Hostettler, Benjamin O’Callaghan, Alaa Khan, Andrea Cortese, Emer O’Connor, Wai Y. Yau, Thomas Bourinaris, Rauan Kaiyrzhanov, Viorica Chelban, Monika Madej, Maria C. Diana, Maria S. Vari, Marina Pedemonte, Claudio Bruno, Ganna Balagura, Marcello Scala, Chiara Fiorillo, Lino Nobili, Nancy T. Malintan, Maria N. Zanetti, Shyam S. Krishnakumar, Gabriele Lignani, James E.C. Jepson, Paolo Broda, Simona Baldassari, Pia Rossi, Floriana Fruscione, Francesca Madia, Monica Traverso, Patrizia De-Marco, Belen Pérez-Dueñas, Francina Munell, Yamna Kriouile, Mohamed El-Khorassani, Blagovesta 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, Gian V. Zuccotti, Michel D. Ferrari, Arn M.J. Van Den Maagdenberg, Alberto Verrotti, Gian L. Marseglia, Salvatore Savasta, Miguel A. Soler, Carmela Scuderi, Eugenia Borgione, Roberto Chimenz, Eloisa Gitto, Valeria Dipasquale, Alessia Sallemi, Monica Fusco, Caterina Cuppari, Maria C. Cutrupi, Martino Ruggieri, Armando Cama, Valeria Capra, Niccolò E. Mencacci, Richard Boles, Neerja Gupta, Madhulika Kabra, Savvas Papacostas, Eleni Zamba-Papanicolaou, Efthymios Dardiotis, Shazia Maqbool, Nuzhat Rana, Osama Atawneh, Shen Y. Lim, Farooq Shaikh, George Koutsis, Marianthi Breza, Domenico A. Coviello, Yves A. Dauvilliers, Issam AlKhawaja, Mariam AlKhawaja, Fuad Al-Mutairi, Tanya Stojkovic, Veronica Ferrucci, Massimo Zollo, Fowzan S. Alkuraya, Maria Kinali, Hamed Sherifa, Hanene Benrhouma, Ilhem B.Y. Turki, Meriem Tazir, Makram Obeid, Sophia Bakhtadze, Nebal W. Saadi, Maha S. Zaki, Chahnez C. Triki, Fabio Benfenati, Stefano Gustincich, Majdi Kara, Vincenzo Belcastro, Nicola Specchio, Giuseppe Capovilla, Ehsan G. Karimiani, Ahmed M. Salih, Njideka U. Okubadejo, Oluwadamilola O. Ojo, Olajumoke O. Oshinaike, Olapeju Oguntunde, Kolawole Wahab, Abiodun H. 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 Haridy, Luca A. Ramenghi, Georgia Xiromerisiou, Emanuele David, Mhammed 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 Benzeev, Federico Zara, Heather C. Mefford, Ingrid E. Scheffer, Jill Clayton-Smith, Alfons Macaya, James E. Rothman, Evan E. Eichler, Dimitri M. Kullmann, Henry Houlden, SYNAPS Study Group

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    43 Citations (Scopus)

    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.

    Original languageEnglish
    Article number3094
    Number of pages16
    JournalNature Communications
    Volume10
    DOIs
    Publication statusPublished - 12 Jul 2019

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