AMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders

  • Nat Commun. 2019 Jul 12;10(1):3094. doi: 10.1038/s41467-019-10910-w.
Vincenzo Salpietro  1  2  3 ,  Christine L Dixon  4 ,  Hui Guo  5  6 ,  Oscar D Bello  4 ,  Jana Vandrovcova  1 ,  Stephanie Efthymiou  1  4 ,  Reza Maroofian  1 ,  Gali Heimer  7 ,  Lydie Burglen  8 ,  Stephanie Valence  9 ,  Erin Torti  10 ,  Moritz Hacke  11 ,  Julia Rankin  12 ,  Huma Tariq  1 ,  Estelle Colin  13  14 ,  Vincent Procaccio  13  14 ,  Pasquale Striano  2  3 ,  Kshitij Mankad  15 ,  Andreas Lieb  4 ,  Sharon Chen  16 ,  Laura Pisani  16 ,  Conceicao Bettencourt  17 ,  Roope Männikkö  1 ,  Andreea Manole  1 ,  Alfredo Brusco  18 ,  Enrico Grosso  18 ,  Giovanni Battista Ferrero  19 ,  Judith Armstrong-Moron  20 ,  Sophie Gueden  21 ,  Omer Bar-Yosef  7 ,  Michal Tzadok  7 ,  Kristin G Monaghan  10 ,  Teresa Santiago-Sim  10 ,  Richard E Person  10 ,  Megan T Cho  10 ,  Rebecca Willaert  10 ,  Yongjin Yoo  22 ,  Jong-Hee Chae  23 ,  Yingting Quan  6 ,  Huidan Wu  6 ,  Tianyun Wang  5  6 ,  Raphael A Bernier  24 ,  Kun Xia  6 ,  Alyssa Blesson  25 ,  Mahim Jain  25 ,  Mohammad M Motazacker  26 ,  Bregje Jaeger  27 ,  Amy L Schneider  28 ,  Katja Boysen  28 ,  Alison M Muir  29 ,  Candace T Myers  30 ,  Ralitza H Gavrilova  31 ,  Lauren Gunderson  31 ,  Laura Schultz-Rogers  31 ,  Eric W Klee  31 ,  David Dyment  32 ,  Matthew Osmond  32  33  34 ,  Mara Parellada  35 ,  Cloe Llorente  36 ,  Javier Gonzalez-Peñas  37 ,  Angel Carracedo  38  39 ,  Arie Van Haeringen  40 ,  Claudia Ruivenkamp  40 ,  Caroline Nava  41 ,  Delphine Heron  41 ,  Rosaria Nardello  42 ,  Michele Iacomino  43 ,  Carlo Minetti  2  3 ,  Aldo Skabar  44 ,  Antonella Fabretto  44 ,  SYNAPS Study Group ,  Miquel Raspall-Chaure  45 ,  Michael Chez  46 ,  Anne Tsai  47 ,  Emily Fassi  48 ,  Marwan Shinawi  48 ,  John N Constantino  49 ,  Rita De Zorzi  50 ,  Sara Fortuna  50 ,  Fernando Kok  51  52 ,  Boris Keren  41 ,  Dominique Bonneau  13  14 ,  Murim Choi  22 ,  Bruria Benzeev  7 ,  Federico Zara  43 ,  Heather C Mefford  29 ,  Ingrid E Scheffer  28 ,  Jill Clayton-Smith  53  54 ,  Alfons Macaya  45 ,  James E Rothman  4  55 ,  Evan E Eichler  5  56 ,  Dimitri M Kullmann  57 ,  Henry Houlden  58
Affiliations
  • 1. Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK.
  • 2. Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto "Giannina Gaslini", 16147, Genoa, Italy.
  • 3. Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 16132, Genoa, Italy.
  • 4. Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK.
  • 5. Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, 98195, USA.
  • 6. Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, 410083, Hunan, China.
  • 7. Pediatric Neurology Unit, Safra Children's Hospital, Sheba Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 526121, Ramat Gan, Israel.
  • 8. Centre de Référence des Malformations et Maladies Congénitales du Cervelet, Département de Génétique et Embryologie Médicale, APHP, Hôpital Trousseau, 75012, Paris, France.
  • 9. Centre de Référence des Malformations et Maladies Congénitales du Cervelet, Service de Neurologie Pédiatrique, APHP, Hôpital Trousseau, 75012, Paris, France.
  • 10. GeneDx, Gaithersburg, MD, 20877, USA.
  • 11. Biochemistry Center, Heidelberg University, D-69120, Heidelberg, Germany.
  • 12. Royal Devon and Exeter NHS Foundation Trust, Exeter, EX1 2ED, UK.
  • 13. Department of Biochemistry and Genetics, University Hospital, 49933, Angers, France.
  • 14. MitoLab, UMR CNRS 6015-INSERM U1083, MitoVasc Institute, Angers University, 49100, Angers, France.
  • 15. Great Ormond Street Hospital for Children, London, WC1N 3JH, UK.
  • 16. Division of Medical Genetics, Northwell Health/Hofstra University SOM, New York, 11020, USA.
  • 17. Department of Clinical and Movement Neurosciences and Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology, London, WC1N 1PJ, UK.
  • 18. Department of Medical Sciences, Medical Genetics Unit, University of Torino, 10126, Torino, Italy.
  • 19. Department of Public Health and Pediatrics, University of Torino, 10126, Torino, Italy.
  • 20. Unit of Medical and Molecular Genetics, University Hospital Sant Joan de Deu Barcelona, 08950, Barcelona, Spain.
  • 21. Unit of Neuropediatrics, University Hospital, Angers Cedex, 49933, France.
  • 22. Department of Biomedical Sciences, Seoul National University, Seoul, 03080, South Korea.
  • 23. Department of Pediatrics, Seoul National University, Seoul, 03080, South Korea.
  • 24. Department of Psychiatry, University of Washington, Seattle, WA, 98195, USA.
  • 25. Center for Autism and Related Disorders, Kennedy Krieger Institute, Baltimore, Maryland, 21211, USA.
  • 26. Department of Clinical Genetics, University of Amsterdam, Meibergdreef 9, 1105, Amsterdam, Netherlands.
  • 27. Department of Pediatric Neurology, Amsterdam UMC, 1105, Amsterdam, Netherlands.
  • 28. Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Melbourne, Victoria, 3084, Australia.
  • 29. Department of Pediatrics, University of Washington, Seattle, WA, 98195, USA.
  • 30. Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, WA, 98195, USA.
  • 31. Department of Clinical Genomics, Mayo Clinic, Rochester, 55902, MN, USA.
  • 32. Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, K1H 8L1, Canada.
  • 33. Department of Human Genetics, McGill University Health Centre, Montréal, QC, H4A 3J1, Canada.
  • 34. Genome Québec Innovation Center, Montréal, QC, H3A 0G1, Canada.
  • 35. Child and Adolescent Psychiatry Department, Hospital General Universitario Gregorio Marañón, School of Medicine, Universidad Complutense, IiSGM, CIBERSAM, 28007, Madrid, Spain.
  • 36. Institute of Psychiatry and Mental Health, Hospital General Universitario Gregorio Maranon, Universidad Complutense, CIBERSAM, 28007, Madrid, Spain.
  • 37. Hospital Gregorio Maranon, IiSGM, School of Medicine, Calle Dr Esquerdo, 46, 28007, Madrid, Spain.
  • 38. 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.
  • 39. Fundación Pública Galega de Medicina Xenómica- IDIS- Servicio Galego de Saúde (SERGAS), 15706, 15782, Santiago de Compostela, Spain.
  • 40. Department of Clinical Genetics, Leiden University Medical Center, 2333 ZA, Leiden, Netherlands.
  • 41. Department of Genetics, Assistance Publique - Hôpitaux de Paris, University Hôpital Pitié-Salpêtrière, 75013, Paris, France.
  • 42. Department of Health Promotion,Mother and Child Care, Internal Medicine and Medical Specialities "G. D'Alessandro", University of Palermo, 90133, Palermo, Italy.
  • 43. Laboratory of Neurogenetics and Neuroscience, IRCCS Istituto "Giannina Gaslini", 16147, Genova, Italy.
  • 44. Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", University of Trieste, 34134, Trieste, Italy.
  • 45. Department of Pediatric Neurology, University Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, 08035, Barcelona, Spain.
  • 46. Neuroscience Medical Group, 1625 Stockton Boulevard, Suite 104, Sacramento, CA, 95816, USA.
  • 47. Department of Genetics and Inherited Metabolic diseases, Children's Hospital Colorado, Aurora, CO, 80045, USA.
  • 48. Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, 63110, USA.
  • 49. William Greenleaf Eliot Division of Child & Adolescent Psychiatry, Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, 63110, USA.
  • 50. Department of Chemical and Pharmaceutical Sciences, University of Trieste, 34134, Trieste, Italy.
  • 51. Neurogenetics Unit, Department of Neurology, University of Sao Paulo, Sao Paulo, 01308-000, Brazil.
  • 52. Mendelics Genomic Analysis, Sao Paulo, SP, 04013-000, Brazil.
  • 53. Centre for Genomic Medicine, Manchester Academic Health Sciences Centre, Central Manchester University Hospitals NHS Foundation Trust, Lancashire, M13 9WL, UK.
  • 54. Division of Evolution and Genomic Sciences, School of Biological Sciences, University of Manchester, Manchester, M13 9WL, UK.
  • 55. Department of Cell Biology, Yale University School of Medicine, New Haven, CT, 06520, USA.
  • 56. Howard Hughes Medical Institute, University of Washington, Seattle, WA, 98195, USA.
  • 57. Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK. [email protected].
  • 58. Department of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK. [email protected].
PMID: 31300657 DOI: 10.1038/s41467-019-10910-w
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.