Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/21360
Title: AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders.
Austin Authors: Salpietro, Vincenzo;Dixon, Christine L;Guo, Hui;Bello, Oscar D;Vandrovcova, Jana;Efthymiou, Stephanie;Maroofian, Reza;Heimer, Gali;Burglen, Lydie;Valence, Stephanie;Torti, Erin;Hacke, Moritz;Rankin, Julia;Tariq, Huma;Colin, Estelle;Procaccio, Vincent;Striano, Pasquale;Mankad, Kshitij;Lieb, Andreas;Chen, Sharon;Pisani, Laura;Bettencourt, Conceicao;Männikkö, Roope;Manole, Andreea;Brusco, Alfredo;Grosso, Enrico;Ferrero, Giovanni Battista;Armstrong-Moron, Judith;Gueden, Sophie;Bar-Yosef, Omer;Tzadok, Michal;Monaghan, Kristin G;Santiago-Sim, Teresa;Person, Richard E;Cho, Megan T;Willaert, Rebecca;Yoo, Yongjin;Chae, Jong-Hee;Quan, Yingting;Wu, Huidan;Wang, Tianyun;Bernier, Raphael A;Xia, Kun;Blesson, Alyssa;Jain, Mahim;Motazacker, Mohammad M;Jaeger, Bregje;Schneider, Amy L ;Boysen, Katja;Muir, Alison M;Myers, Candace T;Gavrilova, Ralitza H;Gunderson, Lauren;Schultz-Rogers, Laura;Klee, Eric W;Dyment, David;Osmond, Matthew;Parellada, Mara;Llorente, Cloe;Gonzalez-Peñas, Javier;Carracedo, Angel;Van Haeringen, Arie;Ruivenkamp, Claudia;Nava, Caroline;Heron, Delphine;Nardello, Rosaria;Iacomino, Michele;Minetti, Carlo;Skabar, Aldo;Fabretto, Antonella;Raspall-Chaure, Miquel;Chez, Michael;Tsai, Anne;Fassi, Emily;Shinawi, Marwan;Constantino, John N;De Zorzi, Rita;Fortuna, Sara;Kok, Fernando;Keren, Boris;Bonneau, Dominique;Choi, Murim;Benzeev, Bruria;Zara, Federico;Mefford, Heather C;Scheffer, Ingrid E ;Clayton-Smith, Jill;Macaya, Alfons;Rothman, James E;Eichler, Evan E;Kullmann, Dimitri M;Houlden, Henry
Affiliation: Division of Medical Genetics, Northwell Health/Hofstra University SOM, New York, 11020, USA
Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK
Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto "Giannina Gaslini", 16147, Genoa, Italy
Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 16132, Genoa, Italy
Grupo de Medicina Xenómica, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), CIMUS, Universidade de Santiago de Compostela, 15782, Santiago de Compostela, Spain
Fundación Pública Galega de Medicina Xenómica- IDIS- Servicio Galego de Saúde (SERGAS), 15706, 15782, Santiago de Compostela, Spain
Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, 410083, Hunan, China
Department of Clinical and Movement Neurosciences and Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology, London, WC1N 1PJ, UK
Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK
Great Ormond Street Hospital for Children, London, WC1N 3JH, UK
Royal Devon and Exeter NHS Foundation Trust, Exeter, EX1 2ED, UK
Department of Genetics, Assistance Publique - Hôpitaux de Paris, University Hôpital Pitié-Salpêtrière, 75013, Paris, France
Unit of Neuropediatrics, University Hospital, Angers Cedex, 49933, France
Department of Biochemistry and Genetics, University Hospital, 49933, Angers, France
MitoLab, UMR CNRS 6015-INSERM U1083, MitoVasc Institute, Angers University, 49100, Angers, France
Centre de Référence des Malformations et Maladies Congénitales du Cervelet, Service de Neurologie Pédiatrique, APHP, Hôpital Trousseau, 75012, Paris, France
Centre de Référence des Malformations et Maladies Congénitales du Cervelet, Département de Génétique et Embryologie Médicale, APHP, Hôpital Trousseau, 75012, Paris, France
Centre for Genomic Medicine, Manchester Academic Health Sciences Centre, Central Manchester University Hospitals NHS Foundation Trust, Lancashire, M13 9WL, UK
Division of Evolution and Genomic Sciences, School of Biological Sciences, University of Manchester, Manchester, M13 9WL, UK
Department of Cell Biology, Yale University School of Medicine, New Haven, CT, 06520, USA
William Greenleaf Eliot Division of Child & Adolescent Psychiatry, Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110, USA
Pediatric Neurology Unit, Safra Children's Hospital, Sheba Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 526121, Ramat Gan, Israel
Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, 98195, USA
Biochemistry Center, Heidelberg University, D-69120, Heidelberg, Germany
GeneDx, Gaithersburg, MD, 20877, USA
Epilepsy Research Centre, Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
Department of Psychiatry, University of Washington, Seattle, WA, 98195, USA
Center for Autism and Related Disorders, Kennedy Krieger Institute, Baltimore, Maryland, 21211, USA
Department of Pediatrics, University of Washington, Seattle, WA, 98195, USA
Neurogenetics Unit, Department of Neurology, University of Sao Paulo, Sao Paulo, 01308-000, Brazil
Mendelics Genomic Analysis, Sao Paulo, SP, 04013-000, Brazil
Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, K1H 8L1, Canada
Department of Human Genetics, McGill University Health Centre, Montréal, QC, H4A 3J1, Canada
Genome Québec Innovation Center, Montréal, QC, H3A 0G1, Canada
Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA, 98195, USA
Department of Clinical Genomics, Mayo Clinic, Rochester, 55902, MN, USA
Neuroscience Medical Group, 1625 Stockton Boulevard, Suite 104, Sacramento, CA, 95816, USA
Department of Genetics and Inherited Metabolic diseases, Children's Hospital Colorado, Aurora, CO, 80045, USA
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, 63110, USA
Howard Hughes Medical Institute, University of Washington, Seattle, WA, 98195, USA
Department of Medical Sciences, Medical Genetics Unit, University of Torino, 10126, Torino, Italy
Department of Public Health and Pediatrics, University of Torino, 10126, Torino, Italy
Unit of Medical and Molecular Genetics, University Hospital Sant Joan de Deu Barcelona, 08950, Barcelona, Spain
Department of Biomedical Sciences, Seoul National University, Seoul, 03080, South Korea
Department of Pediatrics, Seoul National University, Seoul, 03080, South Korea
Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, 410083, Hunan, China
Department of Clinical Genetics, University of Amsterdam, Meibergdreef 9, 1105, Amsterdam, Netherlands.
Department of Pediatric Neurology, Amsterdam UMC, 1105, Amsterdam, Netherlands
Child and Adolescent Psychiatry Department, Hospital General Universitario Gregorio Marañón, School of Medicine, Universidad Complutense, IiSGM, CIBERSAM, 28007, Madrid, Spain
Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Maranon, Universidad Complutense, CIBERSAM, 28007, Madrid, Spain
Hospital Gregorio Maranon, IiSGM, School of Medicine, Calle Dr Esquerdo, 46, 28007, Madrid, Spain
Department of Clinical Genetics, Leiden University Medical Center, 2333 ZA, Leiden, Netherlands
Department of Health Promotion,Mother and Child Care, Internal Medicine and Medical Specialities "G. D'Alessandro", University of Palermo, 90133, Palermo, Italy
Laboratory of Neurogenetics and Neuroscience, IRCCS Istituto "Giannina Gaslini", 16147, Genova, Italy
Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", University of Trieste, 34134, Trieste, Italy
Department of Pediatric Neurology, University Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, 08035, Barcelona, Spain
Department of Chemical and Pharmaceutical Sciences, University of Trieste, 34134, Trieste, Italy
Department of Biomedical Sciences, Seoul National University, Seoul, 03080, South Korea
Laboratory of Neurogenetics and Neuroscience, IRCCS Istituto "Giannina Gaslini", 16147, Genova, Italy
Department of Pediatric Neurology, University Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, 08035, Barcelona, Spain
Issue Date: 12-Jul-2019
metadata.dc.date: 2019-07-12
Publication information: Nature Communications 2019; 10(1): 3094
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.
URI: http://ahro.austin.org.au/austinjspui/handle/1/21360
DOI: 10.1038/s41467-019-10910-w
ORCID: 0000-0001-5701-8365
0000-0003-4900-9877
0000-0002-1119-6809
0000-0003-4530-4537
0000-0001-5790-1051
0000-0001-9567-649X
0000-0001-9090-7690
0000-0002-8727-9184
0000-0002-8318-7231
0000-0001-5260-7187
0000-0002-9420-085X
0000-0002-7222-9985
0000-0002-8059-6064
0000-0002-9195-1455
0000-0002-8246-4014
0000-0001-6696-3545
0000-0002-2866-7777
PubMed URL: 31300657
Type: Journal Article
Appears in Collections:Journal articles

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