AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

SYNAPS Study Group

doi:10.1038/s41467-019-10910-w

AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

SYNAPS Study Group

Neurology

Research output: Contribution to journal › Article › peer-review

142 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 language	English (US)
Article number	3094
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-10910-w
State	Published - Dec 1 2019

Funding

We gratefully acknowledge all the families for their enthusiastic participation to this study. Further acknowledgements can be found in Supplementary Note 29. This study was supported by the Wellcome Trust (WT093205MA and WT104033AIA), Medical Research Council (H.H. and D.M.K.), European Community\u2019s Seventh Framework Programme (FP7/2007\u20102013, under grant agreement No. 2012\u2010305121 to H.H.), Muscular Dystrophy Association (MDA), Muscular Dystrophy UK, The MSA Trust, Ataxia UK, The Sparkes Children\u2019s Medical Research Charity, The Great Ormond Street Hospital Charity, Rosetrees Trust, Brain Research UK, The UK HSP Society, The European Union\u2019s Horizon 2020 research and innovation programme Solve-RD project (No 779257), The Pakistan Council (Scholarship to HT), The National Natural Science Foundation of China (31671114, 81871079, 81330027, and 81525007 to H.G. and K.X.) and the US National Institutes of Health (NIH grant R01MH101221 to E.E.E). E.E.E. is an investigator of the Howard Hughes Medical Institute. We acknowledge the CINECA Awards N. HP10BTJPER, 2017 (to SF), for the availability of high performance computing resources and support. We are also supported by the National Institute for Health Research (NIHR) University College London Hospitals (UCLH) Biomedical Research Centre (BRC). We are grateful to M. Farrant and S. Cull-Candy for helpful suggestions and the stargazin plasmid. We also acknowledge the University of Washington Center for Mendelian Genomics.

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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@article{91449d00a6c14fdfa716401dba4a83a4,

title = "AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders",

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.",

author = "{SYNAPS Study Group} and Vincenzo Salpietro and Dixon, {Christine L.} and Hui Guo and Bello, {Oscar D.} and Jana Vandrovcova and Stephanie Efthymiou and Reza Maroofian and Gali Heimer and Lydie Burglen and Stephanie Valence and Erin Torti and Moritz Hacke and Julia Rankin and Huma Tariq and Estelle Colin and Vincent Procaccio and Pasquale Striano and Kshitij Mankad and Andreas Lieb and Sharon Chen and Laura Pisani and Conceicao Bettencourt and Roope M{\"a}nnikk{\"o} and Andreea Manole and Alfredo Brusco and Enrico Grosso and Ferrero, {Giovanni Battista} and Judith Armstrong-Moron and Sophie Gueden and Omer Bar-Yosef and Michal Tzadok and Monaghan, {Kristin G.} and Teresa Santiago-Sim and Person, {Richard E.} and Cho, {Megan T.} and Rebecca Willaert and Yongjin Yoo and Chae, {Jong Hee} and Yingting Quan and Huidan Wu and Tianyun Wang and Bernier, {Raphael A.} and Kun Xia and Alyssa Blesson and Mahim Jain and Motazacker, {Mohammad M.} and Bregje Jaeger and Schneider, {Amy L.} and Katja Boysen and Mencacci, {Niccol{\`o} E.}",

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = dec,

day = "1",

doi = "10.1038/s41467-019-10910-w",

language = "English (US)",

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T1 - AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

AU - SYNAPS Study Group

AU - Salpietro, Vincenzo

AU - Dixon, Christine L.

AU - Guo, Hui

AU - Bello, Oscar D.

AU - Vandrovcova, Jana

AU - Efthymiou, Stephanie

AU - Maroofian, Reza

AU - Heimer, Gali

AU - Burglen, Lydie

AU - Valence, Stephanie

AU - Torti, Erin

AU - Hacke, Moritz

AU - Rankin, Julia

AU - Tariq, Huma

AU - Colin, Estelle

AU - Procaccio, Vincent

AU - Striano, Pasquale

AU - Mankad, Kshitij

AU - Lieb, Andreas

AU - Chen, Sharon

AU - Pisani, Laura

AU - Bettencourt, Conceicao

AU - Männikkö, Roope

AU - Manole, Andreea

AU - Brusco, Alfredo

AU - Grosso, Enrico

AU - Ferrero, Giovanni Battista

AU - Armstrong-Moron, Judith

AU - Gueden, Sophie

AU - Bar-Yosef, Omer

AU - Tzadok, Michal

AU - Monaghan, Kristin G.

AU - Santiago-Sim, Teresa

AU - Person, Richard E.

AU - Cho, Megan T.

AU - Willaert, Rebecca

AU - Yoo, Yongjin

AU - Chae, Jong Hee

AU - Quan, Yingting

AU - Wu, Huidan

AU - Wang, Tianyun

AU - Bernier, Raphael A.

AU - Xia, Kun

AU - Blesson, Alyssa

AU - Jain, Mahim

AU - Motazacker, Mohammad M.

AU - Jaeger, Bregje

AU - Schneider, Amy L.

AU - Boysen, Katja

AU - Mencacci, Niccolò E.

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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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DO - 10.1038/s41467-019-10910-w

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VL - 10

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 3094

ER -

AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

Abstract

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