AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

SYNAPS Study Group

Research output: Contribution to journalArticlepeer-review


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
Pages (from-to)3094
JournalNature Communications
Issue number1
Publication statusPublished - Jul 12 2019


  • Adolescent
  • Adult
  • Brain/diagnostic imaging
  • Child
  • Child, Preschool
  • Cohort Studies
  • Female
  • Heterozygote
  • Humans
  • Infant
  • Intellectual Disability/genetics
  • Loss of Function Mutation
  • Magnetic Resonance Imaging
  • Male
  • Neurodevelopmental Disorders/diagnostic imaging
  • Receptors, AMPA/genetics
  • Young Adult


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