@article{3025879,
    title = "AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders",
    author = "Salpietro, V. and Dixon, C.L. and Guo, H. and Bello, O.D. and Vandrovcova, J. and Efthymiou, S. and Maroofian, R. and Heimer, G. and Burglen, L. and Valence, S. and Torti, E. and Hacke, M. and Rankin, J. and Tariq, H. and Colin, E. and Procaccio, V. and Striano, P. and Mankad, K. and Lieb, A. and Chen, S. and Pisani, L. and Bettencourt, C. and Männikkö, R. and Manole, A. and Brusco, A. and Grosso, E. and Ferrero, G.B. and Armstrong-Moron, J. and Gueden, S. and Bar-Yosef, O. and Tzadok, M. and Monaghan, K.G. and Santiago-Sim, T. and Person, R.E. and Cho, M.T. and Willaert, R. and Yoo, Y. and Chae, J.-H. and Quan, Y. and Wu, H. and Wang, T. and Bernier, R.A. and Xia, K. and Blesson, A. and Jain, M. and Motazacker, M.M. and Jaeger, B. and Schneider, A.L. and Boysen, K. and Muir, A.M. and Myers, C.T. and Gavrilova, R.H. and Gunderson, L. and Schultz-Rogers, L. and Klee, E.W. and Dyment, D. and Osmond, M. and Parellada, M. and Llorente, C. and Gonzalez-Peñas, J. and Carracedo, A. and Van Haeringen, A. and Ruivenkamp, C. and Nava, C. and Heron, D. and Nardello, R. and Iacomino, M. and Minetti, C. and Skabar, A. and Fabretto, A. and Hanna, M.G. and Bugiardini, E. and Hostettler, I. and O’Callaghan, B. and Khan, A. and Cortese, A. and O’Connor, E. and Yau, W.Y. and Bourinaris, T. and Kaiyrzhanov, R. and Chelban, V. and Madej, M. and Diana, M.C. and Vari, M.S. and Pedemonte, M. and Bruno, C. and Balagura, G. and Scala, M. and Fiorillo, C. and Nobili, L. and Malintan, N.T. and Zanetti, M.N. and Krishnakumar, S.S. and Lignani, G. and Jepson, J.E.C. and Broda, P. and Baldassari, S. and Rossi, P. and Fruscione, F. and Madia, F. and Traverso, M. and De-Marco, P. and Pérez-Dueñas, B. and Munell, F. and Kriouile, Y. and El-Khorassani, M. and Karashova, B. and Avdjieva, D. and Kathom, H. and Tincheva, R. and Van-Maldergem, L. and Nachbauer, W. and Boesch, S. and Gagliano, A. and Amadori, E. and Goraya, J.S. and Sultan, T. and Kirmani, S. and Ibrahim, S. and Jan, F. and Mine, J. and Banu, S. and Veggiotti, P. and Zuccotti, G.V. and Ferrari, M.D. and Van Den Maagdenberg, A.M.J. and Verrotti, A. and Marseglia, G.L. and Savasta, S. and Soler, M.A. and Scuderi, C. and Borgione, E. and Chimenz, R. and Gitto, E. and Dipasquale, V. and Sallemi, A. and Fusco, M. and Cuppari, C. and Cutrupi, M.C. and Ruggieri, M. and Cama, A. and Capra, V. and Mencacci, N.E. and Boles, R. and Gupta, N. and Kabra, M. and Papacostas, S. and Zamba-Papanicolaou, E. and Dardiotis, E. and Maqbool, S. and Rana, N. and Atawneh, O. and Lim, S.Y. and Shaikh, F. and Koutsis, G. and Breza, M. and Coviello, D.A. and Dauvilliers, Y.A. and AlKhawaja, I. and AlKhawaja, M. and Al-Mutairi, F. and Stojkovic, T. and Ferrucci, V. and Zollo, M. and Alkuraya, F.S. and Kinali, M. and Sherifa, H. and Benrhouma, H. and Turki, I.B.Y. and Tazir, M. and Obeid, M. and Bakhtadze, S. and Saadi, N.W. and Zaki, M.S. and Triki, C.C. and Benfenati, F. and Gustincich, S. and Kara, M. and Belcastro, V. and Specchio, N. and Capovilla, G. and Karimiani, E.G. and Salih, A.M. and Okubadejo, N.U. and Ojo, O.O. and Oshinaike, O.O. and Oguntunde, O. and Wahab, K. and Bello, A.H. and Abubakar, S. and Obiabo, Y. and Nwazor, E. and Ekenze, O. and Williams, U. and Iyagba, A. and Taiwo, L. and Komolafe, M. and Senkevich, K. and Shashkin, C. and Zharkynbekova, N. and Koneyev, K. and Manizha, G. and Isrofilov, M. and Guliyeva, U. and Salayev, K. and Khachatryan, S. and Rossi, S. and Silvestri, G. and Haridy, N. and Ramenghi, L.A. and Xiromerisiou, G. and David, E. and Aguennouz, M. and Fidani, L. and Spanaki, C. and Tucci, A. and Raspall-Chaure, M. and Chez, M. and Tsai, A. and Fassi, E. and Shinawi, M. and Constantino, J.N. and De Zorzi, R. and Fortuna, S. and Kok, F. and Keren, B. and Bonneau, D. and Choi, M. and Benzeev, B. and Zara, F. and Mefford, H.C. and Scheffer, I.E. and Clayton-Smith, J. and Macaya, A. and Rothman, J.E. and Eichler, E.E. and Kullmann, D.M. and Houlden, H. and SYNAPS Study Group",
    journal = "Nature Communications",
    year = "2019",
    volume = "10",
    number = "1",
    publisher = "Nature Publishing Group",
    issn = "2041-1723",
    doi = "10.1038/s41467-019-10910-w",
    keywords = "AMPA receptor;  glua1 protein;  glua2 protein;  gria2 protein;  ligand gated ion channel;  unclassified drug;  AMPA receptor;  glutamate receptor ionotropic, AMPA 2, abnormality;  autism;  disability;  gene expression;  genetic analysis;  mutation;  nervous system disorder;  protein, adult;  Article;  autism;  brain disease;  child;  clinical article;  clinical outcome;  controlled study;  current amplitude;  epilepsy;  female;  gene mutation;  heterozygote;  human;  human cell;  intellectual impairment;  male;  mental disease;  missense mutation;  molecular dynamics;  phenotype;  preschool child;  Rett syndrome;  school child;  seizure;  speech disorder;  synaptic transmission;  wild type;  young adult;  adolescent;  brain;  cohort analysis;  diagnostic imaging;  genetics;  infant;  loss of function mutation;  mental disease;  nuclear magnetic resonance imaging, Adolescent;  Adult;  Brain;  Child;  Child, Preschool;  Cohort Studies;  Female;  Heterozygote;  Humans;  Infant;  Intellectual Disability;  Loss of Function Mutation;  Magnetic Resonance Imaging;  Male;  Neurodevelopmental Disorders;  Receptors, AMPA;  Young Adult",
    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. © 2019, The Author(s)."
}