AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

Salpietro, V.; Dixon, C.L.; Guo, H.; Bello, O.D.; Vandrovcova, J.; Efthymiou, S.; ... ; SYNAPS Study Grp (2019)

Article / Letter to editor

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.

• All authors: 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.; Mannikko, 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.T.; Wu, H.D.; Wang, T.Y.; 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-Penas, J.; Carracedo, A.; Haeringen, A. van; Ruivenkamp, C.; Nava, C.; Heron, D.; Nardello, R.; Iacomino, M.; Minetti, C.; Skabar, A.; Fabretto, A.; Chez, M.; Tsai, A.; Fassi, E.; Shinawi, M.; Constantino, J.N.; Zorzi, R. de; 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.; Raspall-Chaure, M.; 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.; Perez-Duenas, 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.; Maagdenberg, A.M.J. van den; 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.; SYNAPS Study Grp
• Date: 2019-07-12
• Journal: Nature Communications
• Volume: 10
• DOI: doi:10.1038/s41467-019-10910-w