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AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

  • Autori: 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; 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
  • Anno di pubblicazione: 2019
  • Tipologia: Articolo in rivista
  • OA Link:


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.