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.

Original languageEnglish
Article number3094
JournalNature Communications
Volume10
Issue number1
DOIs
Publication statusPublished - Dec 1 2019

Fingerprint

AMPA Receptors
mutations
disabilities
Brain Diseases
disorders
Ligand-Gated Ion Channels
Intellectual Disability
Defects
Mutation
causes
defects
Electric potential
seizures
Rett Syndrome
editing
Genes
abnormalities
electric potential
rectification
Membranes

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders. / SYNAPS Study Group.

In: Nature Communications, Vol. 10, No. 1, 3094, 01.12.2019.

Research output: Contribution to journalArticle

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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.",
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AU - Diana, Maria C.

AU - Vari, Maria S.

AU - Pedemonte, Marina

AU - Bruno, Claudio

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AU - Broda, Paolo

AU - Baldassari, Simona

AU - Fruscione, Floriana

AU - Madia, Francesca

AU - Traverso, Monica

AU - De-Marco, Patrizia

AU - Veggiotti, Pierangelo

AU - Marseglia, Gian L.

AU - Savasta, Salvatore

AU - Scuderi, Carmela

AU - Borgione, Eugenia

AU - Cama, Armando

AU - Capra, Valeria

AU - Coviello, Domenico A.

AU - Benfenati, Fabio

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AU - Ramenghi, Luca A.

AU - Zara, Federico

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