AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

Vincenzo Salpietro; Christine Dixon; Hui Guo; Oscar Bello; Jana Vandrovcova; Stephanie Efthymiou; Reza Maroofian; Gali Heimer; Lydie Burglen; Stephanie Valence; Erin Torti; Moritz Hacke; Julia Rankin; Huma Tariq; Estelle Colin; Vincent Procaccio; Pasquale Striano; Kshitij Mankad; Andreas Lieb; Sharon Chen; Laura Pisani; Conceição Bettencourt; Roope Männikkö; Andreea Manole; Alfredo Brusco; Enrico Grosso; Giovanni Battista Ferrero; Judith Armstrong-Moron; Sophie Gueden; Omer Bar-Yosef; Michal Tzadok; Kristin Monaghan; Teresa Santiago-Sim; Richard Person; Megan Cho; Rebecca Willaert; Yongjin Yoo; Jong-Hee Chae; Yingting Quan; Huidan Wu; Tianyun Wang; Raphael Bernier; Kun Xia; Alyssa Blesson; Mahim Jain; Mohammad Motazacker; Bregje Jaeger; Amy Schneider; Katja Boysen; Alison Muir; Candace Myers; Ralitza Gavrilova; Lauren Gunderson; Laura Schultz-Rogers; Eric Klee; David Dyment; Matthew Osmond; Mara Parellada; Cloe Llorente; Javier Gonzalez-Peñas; Angel Carracedo; Arie van Haeringen; Claudia Ruivenkamp; Caroline Nava; Delphine Héron; Rosaria Nardello; Michele Iacomino; Carlo Minetti; Aldo Skabar; Antonella Fabretto; Miquel Raspall-Chaure; Michael Chez; Anne Tsai; Emily Fassi; Marwan Shinawi; John Constantino; Rita de Zorzi; Sara Fortuna; Fernando Kok; Boris Keren; Dominique Bonneau; Murim Choi; Bruria Benzeev; Federico Zara; Heather Mefford; Ingrid Scheffer; Jill Clayton-Smith; Alfons Macaya; James Rothman; Evan Eichler; Dimitri Kullmann; Henry Houlden; Yves Dauvilliers; SYNAPS Study Grp; Fuad Al Mutairi

doi:10.1038/s41467-019-10910-w

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AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

Journal article

Open access

Peer reviewed

AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

Vincenzo Salpietro, Christine Dixon, Hui Guo, Oscar Bello, Jana Vandrovcova, Stephanie Efthymiou, Reza Maroofian, Gali Heimer, Lydie Burglen, Stephanie Valence, …

Nature communications, Vol.10(1), pp.3094-16

12/07/2019

DOI: https://doi.org/10.1038/s41467-019-10910-w

PMCID: PMC6626132

PMID: 31300657

Abstract

Cognitive science

Genetics

Heterozygote

Human health and pathology

Intellectual Disability/genetics

Life Sciences

Neurodevelopmental Disorders/genetics

Neuroscience

Pediatrics

Receptors AMPA/genetics

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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Title: AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders
Creators - without role: Vincenzo Salpietro - University College London
Christine Dixon - University College of London [London]
Hui Guo - University of Washington
Oscar Bello - National Hospital for Neurology and Neurosurgery
Jana Vandrovcova - King‘s College London
Stephanie Efthymiou - National Hospital for Neurology and Neurosurgery
Reza Maroofian - George Institute for Global Health
Gali Heimer - Tel Aviv University
Lydie Burglen - Service de génétique et embryologie médicales [CHU Trousseau]
Stephanie Valence - Service de Neuropédiatrie [CHU Trousseau]
Erin Torti - GeneDx [Gaithersburg, MD, USA]
Moritz Hacke - Heidelberg University Hospital [Heidelberg]
Julia Rankin - Phillips Exeter Academy
Huma Tariq - University College of London [London]
Estelle Colin - Biologie Neurovasculaire et Mitochondriale Intégrée
Vincent Procaccio - Biologie Neurovasculaire et Mitochondriale Intégrée
Pasquale Striano - University of Genoa
Kshitij Mankad - Great Ormond Street Hospital
Andreas Lieb - University College of London [London]
Sharon Chen - University of Sydney
Laura Pisani - Hofstra University
Conceição Bettencourt - University College of London [London]
Roope Männikkö - University College of London [London]
Andreea Manole - University College of London [London]
Alfredo Brusco - University of Turin
Enrico Grosso - University of Turin
Giovanni Battista Ferrero - University of Turin
Judith Armstrong-Moron - Hospital Sant Joan de Déu [Barcelona]
Sophie Gueden - Centre Hospitalier Universitaire d'Angers
Omer Bar-Yosef - Safra Children's Hospital
Michal Tzadok - Safra Children's Hospital
Kristin Monaghan - GeneDx [Gaithersburg, MD, USA]
Teresa Santiago-Sim - GeneDx [Gaithersburg, MD, USA]
Richard Person - GeneDx [Gaithersburg, MD, USA]
Megan Cho - GeneDx [Gaithersburg, MD, USA]
Rebecca Willaert - GeneDx [Gaithersburg, MD, USA]
Yongjin Yoo - Seoul National University Hospital
Jong-Hee Chae - Seoul National University Hospital
Yingting Quan - Central South University [Changsha]
Huidan Wu - Central South University [Changsha]
Tianyun Wang - Central South University [Changsha]
Raphael Bernier - University of Washington
Kun Xia - Central South University [Changsha]
Alyssa Blesson - Kennedy Krieger Institute
Mahim Jain - Kennedy Krieger Institute
Mohammad Motazacker - University of Amsterdam
Bregje Jaeger - University of Amsterdam
Amy Schneider - University of Melbourne
Katja Boysen - University of Melbourne
Alison Muir - University of Washington
Candace Myers - University of Washington
Ralitza Gavrilova - Mayo Clinic
Lauren Gunderson - Mayo Clinic [Rochester]
Laura Schultz-Rogers - Mayo Clinic
Eric Klee - Department of Health Sciences Research [Mayo Clinic]
David Dyment - University of Ottawa
Matthew Osmond - University of British Columbia
Mara Parellada - Universidad Complutense de Madrid
Cloe Llorente - Universidad Complutense de Madrid
Javier Gonzalez-Peñas - Universidad Complutense de Madrid
Angel Carracedo - Universidade de Santiago de Compostela [Spain]
Arie van Haeringen - Universiteit Leiden [Leiden]
Claudia Ruivenkamp - Universiteit Leiden [Leiden]
Caroline Nava - Institut du Cerveau
Delphine Héron - CHU Pitié-Salpêtrière [AP-HP]
Rosaria Nardello - Università degli studi di Palermo - University of Palermo
Michele Iacomino - University of Genoa
Carlo Minetti - University of Genoa
Aldo Skabar - University of Trieste
Antonella Fabretto - University of Trieste
Miquel Raspall-Chaure - Universitat Autònoma de Barcelona
Michael Chez - Department of Neurology and Center for Neuroscience, University of California at Davis, Sacramento
Anne Tsai - Children's Hospital Colorado
Emily Fassi - Washington University in Saint Louis
Marwan Shinawi - Department of Molecular and Human Genetics
John Constantino - Department of Psychiatry
Rita de Zorzi - University of Oxford
Sara Fortuna - University of Trieste
Fernando Kok - Universidade de São Paulo
Boris Keren - Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière]
Dominique Bonneau - Service de Pédiatrie, CHUR Poitiers
Murim Choi - Seoul National University
Bruria Benzeev - Safra Children's Hospital
Federico Zara - Pediatric Neurology and Neuromuscular Diseases Unit
Heather Mefford - University of Washington
Ingrid Scheffer - University of Melbourne
Jill Clayton-Smith - University of Manchester
Alfons Macaya - Universitat Autònoma de Barcelona
James Rothman - Yale School of Medicine
Evan Eichler - University of Washington
Dimitri Kullmann - University College of London [London]
Henry Houlden - University College of London [London]
Yves Dauvilliers - Centre Hospitalier Régional Universitaire [Montpellier]
SYNAPS Study Grp
Fuad Al Mutairi - King Abdulaziz University
Publication Details: Nature communications, Vol.10(1), pp.3094-16
Publisher: Nature Publishing Group
Identifiers: 9920970908331
Academic Unit: King Abdulaziz University; King Saud Bin Abdulaziz University for Health Sciences
Language: English
Resource Type: Journal article