AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

SYNAPS Study Group

Research output: Contribution to journalArticlepeer-review

133 Scopus citations

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
StatePublished - 1 Dec 2019

Funding

FundersFunder number
European Union’s Horizon 2020 research and innovation programme Solve-RD779257
Pakistan Council
Sparkes Children’s Medical Research Charity
National Institutes of Health
National Institute of Mental HealthR01MH101221
National Institute of Mental Health
Muscular Dystrophy Association
Historical Society of Pennsylvania
Wellcome TrustWT104033AIA, WT093205MA
Wellcome Trust
Seventh Framework Programme2012‐305121
Seventh Framework Programme
Muscular Dystrophy UK
Multiple System Atrophy Trust
Brain Research UK
Medical Research Council
National Institute for Health Research
Ataxia UK
Rosetrees Trust
Great Ormond Street Hospital Charity
National Natural Science Foundation of China81330027, 31671114, 81525007, 81871079
National Natural Science Foundation of China
UCLH Biomedical Research Centre

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