| Title: |
AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders |
| Authors: |
Salpietro, V; Dixon, CL; Guo, H; Bello, OD; 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, GB; Armstrong-Moron, J; Gueden, S; Bar-Yosef, O; Tzadok, M; Monaghan, KG; Santiago-Sim, T; Person, RE; Cho, MT; Willaert, R; Yoo, Y; Chae, JH; Quan, Y; Wu, H; Wang, T; Bernier, RA; Xia, K; Blesson, A; Jain, M; Motazacker, MM; Jaeger, B; Schneider, AL; Boysen, K; Muir, AM; Myers, CT; Gavrilova, RH; Gunderson, L; Schultz-Rogers, L; Klee, EW; 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, MG; Bugiardini, E; Hostettler, I; O’Callaghan, B; Khan, A; Cortese, A; O’Connor, E; Yau, WY; Bourinaris, T; Kaiyrzhanov, R; Chelban, V; Madej, M; Diana, MC; Vari, MS; Pedemonte, M; Bruno, C; Balagura, G; Scala, M; Fiorillo, C; Nobili, L; Malintan, NT; Zanetti, MN; Krishnakumar, SS; Lignani, G; Jepson, JEC; Broda, P; Baldassari, S; Rossi, P; Fruscione, F; Madia, F |
| Publisher Information: |
NATURE PORTFOLIO |
| Publication Year: |
2019 |
| Collection: |
The University of Melbourne: Digital Repository |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| ISSN: |
2041-1723 |
| Relation: |
https://hdl.handle.net/11343/246204 |
| Availability: |
https://hdl.handle.net/11343/246204 |
| Rights: |
https://creativecommons.org/licenses/by/4.0 ; CC BY |
| Accession Number: |
edsbas.BA62EE22 |
| Database: |
BASE |