AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders
Authors: 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 ,   SYNAPS Study Group, Hanna Michael G. , Bugiardini Enrico , Hostettler Isabel , O’Callaghan Benjamin , Khan Alaa , Cortese Andrea , O’Connor Emer , Yau Wai Y. , Bourinaris Thomas , Kaiyrzhanov Rauan , Chelban Viorica , Madej Monika , Diana Maria C. , Vari Maria S. , Pedemonte Marina , Bruno Claudio , Balagura Ganna , Scala Marcello , Fiorillo Chiara , Nobili Lino , Malintan Nancy T. , Zanetti Maria N. , Krishnakumar Shyam S. , Lignani Gabriele , Jepson James E. C. , Broda Paolo , Baldassari Simona , Rossi Pia , Fruscione Floriana , Madia Francesca , Traverso Monica , De-Marco Patrizia , Pérez-Dueñas Belen , Munell Francina , Kriouile Yamna , El-Khorassani Mohamed , Karashova Blagovesta , Avdjieva Daniela , Kathom Hadil , Tincheva Radka , Van-Maldergem Lionel , Nachbauer Wolfgang , Boesch Sylvia , Gagliano Antonella , Amadori Elisabetta , Goraya Jatinder S. , Sultan Tipu , Kirmani Salman , Ibrahim Shahnaz , Jan Farida , Mine Jun , Banu Selina , Veggiotti Pierangelo , Zuccotti Gian V. , Ferrari Michel D. , Van Den Maagdenberg Arn M. J. , Verrotti Alberto , Marseglia Gian L. , Savasta Salvatore , Soler Miguel A. , Scuderi Carmela , Borgione Eugenia , Chimenz Roberto , Gitto Eloisa , Dipasquale Valeria , Sallemi Alessia , Fusco Monica , Cuppari Caterina , Cutrupi Maria C. , Ruggieri Martino , Cama Armando , Capra Valeria , Mencacci Niccolò E. , Boles Richard , Gupta Neerja , Kabra Madhulika , Papacostas Savvas , Zamba-Papanicolaou Eleni , Dardiotis Efthymios , Maqbool Shazia , Rana Nuzhat , Atawneh Osama , Lim Shen Y. , Shaikh Farooq , Koutsis George , Breza Marianthi , Coviello Domenico A. , Dauvilliers Yves A. , AlKhawaja Issam , AlKhawaja Mariam , Al-Mutairi Fuad , Stojkovic Tanya , Ferrucci Veronica , Zollo Massimo , Alkuraya Fowzan S. , Kinali Maria , Sherifa Hamed , Benrhouma Hanene , Turki Ilhem B. Y. , Tazir Meriem , Obeid Makram , Bakhtadze Sophia , Saadi Nebal W. , Zaki Maha S. , Triki Chahnez C. , Benfenati Fabio , Gustincich Stefano , Kara Majdi , Belcastro Vincenzo , Specchio Nicola , Capovilla Giuseppe , Karimiani Ehsan G. , Salih Ahmed M. , Okubadejo Njideka U. , Ojo Oluwadamilola O. , Oshinaike Olajumoke O. , Oguntunde Olapeju , Wahab Kolawole , Bello Abiodun H. , Abubakar Sanni , Obiabo Yahaya , Nwazor Ernest , Ekenze Oluchi , Williams Uduak , Iyagba Alagoma , Taiwo Lolade , Komolafe Morenikeji , Senkevich Konstantin , Shashkin Chingiz , Zharkynbekova Nazira , Koneyev Kairgali , Manizha Ganieva , Isrofilov Maksud , Guliyeva Ulviyya , Salayev Kamran , Khachatryan Samson , Rossi Salvatore , Silvestri Gabriella , Haridy Nourelhoda , Ramenghi Luca A. , Xiromerisiou Georgia , David Emanuele , Aguennouz Mhammed , Fidani Liana , Spanaki Cleanthe , Tucci Arianna , 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 
Published: July 2019

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.