Ερευνητικό υλικό ΕΚΠΑ

AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

Αγγλικά

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).

2019

Salpietro, V.
Dixon, C.L.
Guo, H.
Bello, O.D.
Vandrovcova, J.
Efthymiou, S.
Maroofian, R.
Heimer, G.
Burglen, L.
Valence, S.
Torti, E.
Hacke, M.
Rankin, J.
Tariq, H.
Colin, E.
Procaccio, V.
Striano, P.
Mankad, K.
Lieb, A.
Chen, S.
Pisani, L.
Bettencourt, C.
Männikkö, R.
Manole, A.
Brusco, A.
Grosso, E.
Ferrero, G.B.
Armstrong-Moron, J.
Gueden, S.
Bar-Yosef, O.
Tzadok, M.
Monaghan, K.G.
Santiago-Sim, T.
Person, R.E.
Cho, M.T.
Willaert, R.
Yoo, Y.
Chae, J.-H.
Quan, Y.
Wu, H.
Wang, T.
Bernier, R.A.
Xia, K.
Blesson, A.
Jain, M.
Motazacker, M.M.
Jaeger, B.
Schneider, A.L.
Boysen, K.
Muir, A.M.
Myers, C.T.
Gavrilova, R.H.
Gunderson, L.
Schultz-Rogers, L.
Klee, E.W.
Dyment, D.
Osmond, M.
Parellada, M.
Llorente, C.
Gonzalez-Peñas, J.
Carracedo, A.
Van Haeringen, A.
Ruivenkamp, C.
Nava, C.
Heron, D.
Nardello, R.
Iacomino, M.
Minetti, C.
Skabar, A.
Fabretto, A.
Hanna, M.G.
Bugiardini, E.
Hostettler, I.
O’Callaghan, B.
Khan, A.
Cortese, A.
O’Connor, E.
Yau, W.Y.
Bourinaris, T.
Kaiyrzhanov, R.
Chelban, V.
Madej, M.
Diana, M.C.
Vari, M.S.
Pedemonte, M.
Bruno, C.
Balagura, G.
Scala, M.
Fiorillo, C.
Nobili, L.
Malintan, N.T.
Zanetti, M.N.
Krishnakumar, S.S.
Lignani, G.
Jepson, J.E.C.
Broda, P.
Baldassari, S.
Rossi, P.
Fruscione, F.
Madia, F.
Traverso, M.
De-Marco, P.
Pérez-Dueñas, B.
Munell, F.
Kriouile, Y.
El-Khorassani, M.
Karashova, B.
Avdjieva, D.
Kathom, H.
Tincheva, R.
Van-Maldergem, L.
Nachbauer, W.
Boesch, S.
Gagliano, A.
Amadori, E.
Goraya, J.S.
Sultan, T.
Kirmani, S.
Ibrahim, S.
Jan, F.
Mine, J.
Banu, S.
Veggiotti, P.
Zuccotti, G.V.
Ferrari, M.D.
Van Den Maagdenberg, A.M.J.
Verrotti, A.
Marseglia, G.L.
Savasta, S.
Soler, M.A.
Scuderi, C.
Borgione, E.
Chimenz, R.
Gitto, E.
Dipasquale, V.
Sallemi, A.
Fusco, M.
Cuppari, C.
Cutrupi, M.C.
Ruggieri, M.
Cama, A.
Capra, V.
Mencacci, N.E.
Boles, R.
Gupta, N.
Kabra, M.
Papacostas, S.
Zamba-Papanicolaou, E.
Dardiotis, E.
Maqbool, S.
Rana, N.
Atawneh, O.
Lim, S.Y.
Shaikh, F.
Koutsis, G.
Breza, M.
Coviello, D.A.
Dauvilliers, Y.A.
AlKhawaja, I.
AlKhawaja, M.
Al-Mutairi, F.
Stojkovic, T.
Ferrucci, V.
Zollo, M.
Alkuraya, F.S.
Kinali, M.
Sherifa, H.
Benrhouma, H.
Turki, I.B.Y.
Tazir, M.
Obeid, M.
Bakhtadze, S.
Saadi, N.W.
Zaki, M.S.
Triki, C.C.
Benfenati, F.
Gustincich, S.
Kara, M.
Belcastro, V.
Specchio, N.
Capovilla, G.
Karimiani, E.G.
Salih, A.M.
Okubadejo, N.U.
Ojo, O.O.
Oshinaike, O.O.
Oguntunde, O.
Wahab, K.
Bello, A.H.
Abubakar, S.
Obiabo, Y.
Nwazor, E.
Ekenze, O.
Williams, U.
Iyagba, A.
Taiwo, L.
Komolafe, M.
Senkevich, K.
Shashkin, C.
Zharkynbekova, N.
Koneyev, K.
Manizha, G.
Isrofilov, M.
Guliyeva, U.
Salayev, K.
Khachatryan, S.
Rossi, S.
Silvestri, G.
Haridy, N.
Ramenghi, L.A.
Xiromerisiou, G.
David, E.
Aguennouz, M.
Fidani, L.
Spanaki, C.
Tucci, A.
Raspall-Chaure, M.
Chez, M.
Tsai, A.
Fassi, E.
Shinawi, M.
Constantino, J.N.
De Zorzi, R.
Fortuna, S.
Kok, F.
Keren, B.
Bonneau, D.
Choi, M.
Benzeev, B.
Zara, F.
Mefford, H.C.
Scheffer, I.E.
Clayton-Smith, J.
Macaya, A.
Rothman, J.E.
Eichler, E.E.
Kullmann, D.M.
Houlden, H.
SYNAPS Study Group

Nature Communications

Nature Publishing Group

10

1

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

https://doi.org/10.1038/s41467-019-10910-w

10.1038/s41467-019-10910-w

https://pergamos.lib.uoa.gr/uoa/dl/object/3025879