AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

Vincenzo Salpietro, Christine L. Dixon, Hui Guo, Oscar D. 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, Conceicao Bettencourt, Roope Männikkö, Andreea Manole, Alfredo Brusco, Enrico Grosso, Giovanni Battista Ferrero, Judith Armstrong-Moron, Sophie Gueden, Omer Bar-Yosef, Michal Tzadok, Kristin G. Monaghan, Teresa Santiago-Sim, Richard E. Person, Megan T. Cho, Rebecca Willaert, Yongjin Yoo, Jong-Hee Chae, Yingting Quan, Huidan Wu, Tianyun Wang, Raphael A. Bernier, Kun Xia, Alyssa Blesson, Mahim Jain, Mohammad M. Motazacker, Bregje Jaeger, Amy L. Schneider, Katja Boysen, Alison M. Muir, Candace T. Myers, Ralitza H. Gavrilova, Lauren Gunderson, Laura Schultz-Rogers, Eric W. Klee, David Dyment, Matthew Osmond, Mara Parellada, Cloe Llorente, Javier Gonzalez-Peñas, Angel Carracedo, Arie Haeringen, Claudia Ruivenkamp, Caroline Nava, Delphine Heron, Rosaria Nardello, Michele Iacomino, Carlo Minetti, Aldo Skabar, Antonella Fabretto, Miquel Raspall-Chaure, Michael Chez, Anne Tsai, Emily Fassi, Marwan Shinawi, John N. Constantino, Rita De Zorzi, Sara Fortuna, Fernando Kok, Boris Keren, Dominique Bonneau, Murim Choi, Bruria Benzeev, Federico Zara, Heather C. Mefford, Ingrid E. Scheffer, Jill Clayton-Smith, Alfons Macaya, James E. Rothman, Evan E. Eichler, Dimitri M. Kullmann () and Henry Houlden ()
Additional contact information
Vincenzo Salpietro: UCL Queen Square Institute of Neurology
Christine L. Dixon: UCL Queen Square Institute of Neurology
Hui Guo: University of Washington School of Medicine
Oscar D. Bello: UCL Queen Square Institute of Neurology
Jana Vandrovcova: UCL Queen Square Institute of Neurology
Stephanie Efthymiou: UCL Queen Square Institute of Neurology
Reza Maroofian: UCL Queen Square Institute of Neurology
Gali Heimer: Tel Aviv University
Lydie Burglen: Centre de Référence des Malformations et Maladies Congénitales du Cervelet, Département de Génétique et Embryologie Médicale, APHP, Hôpital Trousseau
Stephanie Valence: Centre de Référence des Malformations et Maladies Congénitales du Cervelet, Service de Neurologie Pédiatrique, APHP, Hôpital Trousseau
Erin Torti: GeneDx
Moritz Hacke: Heidelberg University
Julia Rankin: Royal Devon and Exeter NHS Foundation Trust
Huma Tariq: UCL Queen Square Institute of Neurology
Estelle Colin: University Hospital
Vincent Procaccio: University Hospital
Pasquale Striano: Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto “Giannina Gaslini”
Kshitij Mankad: Great Ormond Street Hospital for Children
Andreas Lieb: UCL Queen Square Institute of Neurology
Sharon Chen: Northwell Health/Hofstra University SOM
Laura Pisani: Northwell Health/Hofstra University SOM
Conceicao Bettencourt: Department of Clinical and Movement Neurosciences and Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology
Roope Männikkö: UCL Queen Square Institute of Neurology
Andreea Manole: UCL Queen Square Institute of Neurology
Alfredo Brusco: University of Torino
Enrico Grosso: University of Torino
Giovanni Battista Ferrero: University of Torino
Judith Armstrong-Moron: University Hospital Sant Joan de Deu Barcelona
Sophie Gueden: University Hospital
Omer Bar-Yosef: Tel Aviv University
Michal Tzadok: Tel Aviv University
Kristin G. Monaghan: GeneDx
Teresa Santiago-Sim: GeneDx
Richard E. Person: GeneDx
Megan T. Cho: GeneDx
Rebecca Willaert: GeneDx
Yongjin Yoo: Seoul National University
Jong-Hee Chae: Seoul National University
Yingting Quan: Central South University
Huidan Wu: Central South University
Tianyun Wang: University of Washington School of Medicine
Raphael A. Bernier: University of Washington
Kun Xia: Central South University
Alyssa Blesson: Center for Autism and Related Disorders, Kennedy Krieger Institute
Mahim Jain: Center for Autism and Related Disorders, Kennedy Krieger Institute
Mohammad M. Motazacker: University of Amsterdam
Bregje Jaeger: Amsterdam UMC
Amy L. Schneider: University of Melbourne, Austin Health, Melbourne
Katja Boysen: University of Melbourne, Austin Health, Melbourne
Alison M. Muir: University of Washington
Candace T. Myers: University of Washington
Ralitza H. Gavrilova: Mayo Clinic
Lauren Gunderson: Mayo Clinic
Laura Schultz-Rogers: Mayo Clinic
Eric W. Klee: Mayo Clinic
David Dyment: University of Ottawa
Matthew Osmond: University of Ottawa
Mara Parellada: Hospital General Universitario Gregorio Marañón, School of Medicine, Universidad Complutense, IiSGM, CIBERSAM
Cloe Llorente: Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Maranon, Universidad Complutense, CIBERSAM
Javier Gonzalez-Peñas: Hospital Gregorio Maranon, IiSGM, School of Medicine, Calle Dr Esquerdo, 46
Angel Carracedo: Grupo de Medicina Xenómica, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), CIMUS, Universidade de Santiago de Compostela
Arie Haeringen: Leiden University Medical Center
Claudia Ruivenkamp: Leiden University Medical Center
Caroline Nava: University Hôpital Pitié-Salpêtrière
Delphine Heron: University Hôpital Pitié-Salpêtrière
Rosaria Nardello: University of Palermo
Michele Iacomino: Laboratory of Neurogenetics and Neuroscience, IRCCS Istituto “Giannina Gaslini”
Carlo Minetti: Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto “Giannina Gaslini”
Aldo Skabar: University of Trieste
Antonella Fabretto: University of Trieste
Miquel Raspall-Chaure: University Hospital Vall d’Hebron, Universitat Autònoma de Barcelona
Michael Chez: Neuroscience Medical Group, 1625 Stockton Boulevard, Suite 104
Anne Tsai: Children’s Hospital Colorado
Emily Fassi: Washington University School of Medicine
Marwan Shinawi: Washington University School of Medicine
John N. Constantino: Washington University School of Medicine
Rita De Zorzi: University of Trieste
Sara Fortuna: University of Trieste
Fernando Kok: University of Sao Paulo
Boris Keren: University Hôpital Pitié-Salpêtrière
Dominique Bonneau: University Hospital
Murim Choi: Seoul National University
Bruria Benzeev: Tel Aviv University
Federico Zara: Laboratory of Neurogenetics and Neuroscience, IRCCS Istituto “Giannina Gaslini”
Heather C. Mefford: University of Washington
Ingrid E. Scheffer: University of Melbourne, Austin Health, Melbourne
Jill Clayton-Smith: Central Manchester University Hospitals NHS Foundation Trust
Alfons Macaya: University Hospital Vall d’Hebron, Universitat Autònoma de Barcelona
James E. Rothman: UCL Queen Square Institute of Neurology
Evan E. Eichler: University of Washington School of Medicine
Dimitri M. Kullmann: UCL Queen Square Institute of Neurology
Henry Houlden: UCL Queen Square Institute of Neurology

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10910-w

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