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AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders.

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

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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
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:
DateEvent
12 July 2019Published
22 May 2019Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
WT093205MAWellcome Trusthttp://dx.doi.org/10.13039/100004440
R01 MH101221NIMH NIH HHSUNSPECIFIED
WT104033AIAWellcome Trusthttp://dx.doi.org/10.13039/100004440
2012‐305121Seventh Framework Programmehttp://dx.doi.org/10.13039/501100004963
779257Horizon 2020UNSPECIFIED
31671114National Natural Science Foundation of Chinahttp://dx.doi.org/10.13039/501100001809
81871079National Natural Science Foundation of Chinahttp://dx.doi.org/10.13039/501100001809
81330027National Natural Science Foundation of Chinahttp://dx.doi.org/10.13039/501100001809
81525007National Natural Science Foundation of Chinahttp://dx.doi.org/10.13039/501100001809
N. HP10BTJPERCINECAUNSPECIFIED
PubMed ID: 31300657
Web of Science ID: WOS:000475295700001
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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