AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

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art_SALPIETRO_AMPA_receptor_GluA2_subunit_defects_are_a_cause_2019.PDF (3.43 MB)
Citações na Scopus
131
Tipo de produção
article
Data de publicação
2019
DOI
Scopus
Web of Science
PubMed
Título da Revista
ISSN da Revista
Título do Volume
Editora
NATURE PUBLISHING GROUP
Autores
SALPIETRO, Vincenzo
DIXON, Christine L.
GUO, Hui
BELLO, Oscar D.
VANDROVCOVA, Jana
EFTHYMIOU, Stephanie
MAROOFIAN, Reza
HEIMER, Gali
BURGLEN, Lydie
VALENCE, Stephanie
Citação
NATURE COMMUNICATIONS, v.10, article ID 3094, 16p, 2019
Projetos de Pesquisa
Unidades Organizacionais
Fascículo
Resumo
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.
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URI
https://observatorio.fm.usp.br/handle/OPI/33116
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Coleções
Artigos e Materiais de Revistas Científicas - FM/MNE
Artigos e Materiais de Revistas Científicas - LIM/15