Salpietro, V;
Dixon, CL;
Guo, H;
Bello, OD;
Vandrovcova, J;
Efthymiou, S;
Maroofian, R;
Heimer, G;
Burglen, L;
Valence, S;
et al.
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, J-H; 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; SYNAPS Study Group; Raspall-Chaure, M; Chez, M; Tsai, A; Fassi, E; Shinawi, M; Constantino, JN; De Zorzi, R; Fortuna, S; Kok, F; Keren, B; Bonneau, D; Choi, M; Benzeev, B; Zara, F; Mefford, HC; Scheffer, IE; Clayton-Smith, J; Macaya, A; Rothman, JE; Eichler, EE; Kullmann, DM; Houlden, H
(2019)
AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders.
Nat Commun, 10 (1).
p. 3094.
ISSN 2041-1723
https://doi.org/10.1038/s41467-019-10910-w
SGUL Authors: Maroofian, Reza
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.
Item Type: |
Article
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Additional Information: |
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
Keywords: |
SYNAPS Study Group, MD Multidisciplinary |
SGUL Research Institute / Research Centre: |
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) |
Journal or Publication Title: |
Nat Commun |
ISSN: |
2041-1723 |
Language: |
eng |
Dates: |
Date | Event |
---|
12 July 2019 | Published | 22 May 2019 | Accepted |
|
Publisher License: |
Creative Commons: Attribution 4.0 |
Projects: |
|
PubMed ID: |
31300657 |
Web of Science ID: |
WOS:000475295700001 |
![](http://static.pubmed.gov/portal/portal3rc.fcgi/2745237/img/27842) |
Go to PubMed abstract |
URI: |
https://openaccess.sgul.ac.uk/id/eprint/111214 |
Publisher's version: |
https://doi.org/10.1038/s41467-019-10910-w |
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