Data di Pubblicazione:
2019
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.
Tipologia CRIS:
14.a.1 Articolo su rivista
Keywords:
Ion channel in the nervous system, Developmental disorders, Synaptic development, NG sequencing
Elenco autori:
Salpietro, Vincenzo; Dixon, Christine L.; Guo, Hui; Bello, Oscar D.; Vandrovcova, Jana; Efthymiou, Stephani; Maroofian, Reza; Heimer, Gali; Burglen, Lydie; Valence, Stephanie; Torti, Erin; Hacke, Moritz; Rankin, Julia; Tariq, Huma; Colin, Estelle; Procaccio, Vincent; Striano, Pasquale; Mankad, Kshitij; Lieb, Andreas; Chen, Sharon; Pisani, Laura; Bettencourt, Conceicao; Mannikko, Roope; Manole, Andreea; Brusco, Alfredo; Grosso, Enrico; Ferrero, Giovanni Battista; Armstrong-Moron, Judith; Gueden, Sophie; Bar-Yosef, Omer; Tzadok, Michal; Monaghan, Kristin G.; Santiago-Sim, Teresa; Person, Richard E.; Cho, Megan T.; Willaert, Rebecca; Yoo, Yongjin; Chae, Jong-Hee; Quan, Yingting; Wu, Huidan; Wang, Tianyun; Bernier, Raphael A.; Xia, Kun; Blesson, Alyssa; Jain, Mahim; Motazacker, Mohammad M.; Jaeger, Bregje; Schneider, Amy L.; Boysen, Katja; Muir, Alison M.; Myers, Candace T.; Gavrilova, Ralitza H.; Gunderson, Lauren; Schultz-Rogers, Laura; Klee, Eric W.; Dyment, David; Osmond, Matthew; Parellada, Mara; Llorente, Cloe; Gonzalez-Penas, Javier; Carracedo, Angel; Van Haeringen, Arie; Ruivenkamp, Claudia; Nava, Caroline; Heron, Delphine; Nardello, Rosaria; Iacomino, Michele; Minetti, Carlo; Skabar, Aldo; Fabretto, Antonella; Chez, Michael; Tsai, Anne; Fassi, Emily; Shinawi, Marwan; Constantino, John N.; De Zorzi, Rita; Fortuna, Sara; Kok, Fernando; Keren, Boris; Bonneau, Dominique; Choi, Murim; Benzeev, Bruria; Zara, Federico; Mefford, Heather C.; Scheffer, Ingrid E.; Clayton-Smith, Jill; Macaya, Alfons); Rothman, James E.; Eichler, Evan E.; Kullmann, Dimitri M.; Houlden, Henry; Chimenz, Roberto; Gitto, Eloisa; Aguennouz, Mhammed
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