AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders.
Vincenzo SalpietroChristine L DixonHui GuoOscar D BelloJana VandrovcovaStephanie EfthymiouReza MaroofianGali HeimerLydie BurglenStéphanie ValenceErin TortiMoritz HackeJulia RankinHuma TariqEstelle ColinVincent ProcaccioPasquale StrianoKshitij MankadAndreas LiebSharon ChenLaura PisaniConceicao BettencourtRoope MannikkoAndreea ManoleAlfredo BruscoEnrico GrossoGiovanni Battista FerreroJudith Armstrong-MoronSophie GuedenOmer Bar-YosefMichal TzadokKristin G MonaghanTeresa Santiago-SimRichard E PersonMegan T ChoRebecca WillaertYongjin YooJong-Hee ChaeYingting QuanHuidan WuTianyun WangRaphael A BernierKun XiaAlyssa BlessonMahim JainMohammad M MotazackerBregje JaegerAmy L SchneiderKatja BoysenAlison M MuirCandace T MyersRalitza H GavrilovaLauren GundersonLaura E Schultz-RogersEric W KleeDavid DymentMatthew OsmondMara ParelladaCloe LlorenteJavier Gonzalez-PeñasAngel CarracedoArie Van HaeringenClaudia RuivenkampCaroline NavaDelphine HeronRosaria NardelloMichele IacominoCarlo MinettiAldo SkabarAntonella Fabrettonull nullMiquel Raspall-ChaureMichael ChezAnne TsaiEmily FassiMarwan ShinawiJohn N ConstantinoRita De ZorziSara FortunaFernando KokBoris KerenDominique BonneauMurim ChoiBruria BenzeevFederico ZaraHeather C MeffordIngrid E SchefferJill Clayton-SmithAlfons MacayaJames E RothmanEvan E EichlerDimitri Michael KullmannHenry HouldenPublished in: Nature communications (2019)
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.
Keyphrases
- autism spectrum disorder
- intellectual disability
- wild type
- attention deficit hyperactivity disorder
- early onset
- copy number
- crispr cas
- genome wide
- poor prognosis
- gene expression
- congenital heart disease
- transcription factor
- protein kinase
- binding protein
- long non coding rna
- dna methylation
- functional connectivity
- case control