Missense variants in RPH3A cause defects in excitatory synaptic function and are associated with a clinically variable neurodevelopmental disorder |
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| Affiliation: | 1. Department of Medical Sciences, University of Turin, Turin, Italy;2. Institute of Oncology Research (IOR), Bellinzona, Switzerland;3. Università della Svizzera Italiana, Lugano, Switzerland;4. Department of Pharmacological and Biomolecular Sciences, DiSFeB, University of the Studies of Milan, Milan, Italy;5. Department of Neuroscience, University of Turin, Turin, Italy;6. William Harvey Research Institute, Clinical Pharmacology Precision Medicine, Queen Mary University of London, Charterhouse Square, United Kingdom;7. Department of Biosciences, University of the Studies of Milan, Milan, Italy;8. Institute of Biophysics, Consiglio Nazionale delle Ricerche (CNR), Milan, Italy;9. Department of Drug Science and Technology, University of Turin, Turin, Italy;10. Department of Pediatrics, Regina Margherita Children Hospital, Turin, Italy;11. HudsonAlpha Institute for Biotechnology, Huntsville, AL;12. Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, United Kingdom;13. Chalfont Centre for Epilepsy Bucks, Chalfont St Peter, United Kingdom;14. Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom;15. Department of Paediatric and Child Health, Aga Khan University Hospital, Karachi, Pakistan;16. University College London, UCL Queen Square Institute of Neurology, London, United Kingdom;17. Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy;18. Department of Public Health and Pediatric Sciences, University of Torino, Torino, Italy;19. Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy;20. Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY;21. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY;22. The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY;23. Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY;24. Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY;25. Department of Clinical and Biological Sciences, University of Turin, Orbassano, TO, Italy;26. Medical Genetics Unit, Città della Salute e della Scienza University Hospital, Turin, Italy;1. Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia;2. Division of Maternal-Fetal Medicine, Brigham and Women’s Hospital, Boston, MA;3. Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, TX;4. Divisions of Newborn Medicine and Genetics and Genomics, Boston Children’s Hospital, Boston, MA;5. Medical Genetics, Department of Pediatrics, Mass General for Children, Boston, MA;1. Division of Medical Genetics, Department of Specialized Medicine, Montreal Children''s Hospital, McGill University Health Centre (MUHC), Montreal, Canada;2. Department of Human Genetics, McGill University, Montreal, QC, Canada;3. Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK;4. Neuroradiology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy;5. Goodman Cancer Institute, McGill University, Montreal, Canada;6. Department of Biochemistry, McGill University, Montreal, Canada;7. Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom;8. University of South Dakota Sanford School of Medicine Sioux Falls, SD;9. Sanford Research, Pediatrics and Rare Diseases Group, Sioux Falls, SD;10. Human Genetics and Genome Research Institute, Clinical Genetics Department, National Research Centre, Cairo, Egypt;11. Department of Genetics, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman;12. Genetic and Developmental Medicine Clinic, Sultan Qaboos University Hospital, Muscat, Oman;13. Indira Gandhi Institute of Child Health, Bangalore, India;14. Department of Pediatrics, University of Arkansas for Medical Sciences, Little Rock, AR;15. Unit of Pediatric Neurology, COALA (Center for Diagnosis and Treatment of Leukodystrophies), V. Buzzi Children''s Hospital, Milan, Italy;16. Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy;17. Pediatric Radiology and Neuroradiology Department, Children''s Hospital Vittore Buzzi, Milan, Italy;18. Department of Pediatrics and Adolescent Medicine, University Medical Center Göttingen, Germany;19. Centro de Obsetricia y Ginecologia & Centro Medico Moderno, Santo Domingo, Dominican Republic;20. Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy;21. Division of Neonatology, Cincinnati Children''s Hospital Medical Center, Cincinnati, OH;22. Centro de Obsetricia y Ginecologia, Santo Domingo, Dominican Republic;23. Service de Génétique Médicale, CHU de Nantes, Nantes Université, Nantes, France;24. Nantes Université, CNRS, INSERM, l''Institut du Thorax, Nantes, France;25. University of Angers, MitoLab Team, Unité MitoVasc, UMR CNRS 6015, INSERM U1083, SFR ICAT, Angers, France;26. Department of Genetics, CHU Angers, Angers, France;27. GeneDx, Gaithersburg, MD;28. Human Genetic center Tübingen, Baden-Württemberg, Germany;29. CeGaT GmbH, Germany;30. Department of Neurology, Hospital de Pediatría Juan P. Garrahan, Buenos Aires, Argentina;31. Genomics Laboratory, Hospital de Pediatría Juan P. Garrahan, Buenos Aires, Argentina;32. Department of Biotechnological and Applied Clinical Sciences, University of L''Aquila, L''Aquila, Italy;33. Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom;34. West Midlands Regional Genetics Service, Birmingham Women and Children''s Hospital NHS Foundation Trust, Birmingham, United Kingdom;35. Children’s Hospital of the King’s Daughters, Norfolk, Virginia, VA;36. Department of Genetics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark;37. Department of Neurology, Washington University School of Medicine, St. Louis, MO;38. Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO;39. Center for the Investigation of Membrane Excitability Diseases (CIMED), St. Louis, MO;40. Rainbow Children Hospital, Hyderabad, India;41. Division of Medical Genetics, Nemours/A I duPont Hospital for Children, Wilmington, DE;42. Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom;43. Service de Génétique Médicale, CHU de Nantes, Nantes Université, Nantes, France;44. Nantes Université, CNRS, INSERM, l''Institut du Thorax, Nantes, France;45. Department of Child Neurology, University Hospital, Gießen, Germany;46. Patrick G. Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast, United Kingdom;47. Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark;48. Division of Genetics, Genomics, and Metabolism, Ann & Robert Lurie Children''s Hospital of Chicago, Chicago;49. Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago;50. Fundacion Cardiovascular de Colombia, Floridablanca, Colombia;51. Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy;52. Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom;53. NHS Highly Specialized Service for Rare Mitochondrial Disorders of Adults and Children, Newcastle University, Newcastle upon Tyne, United Kingdom;54. ARNA - UMR5320 CNRS - U1212 INSERM, Université de Bordeaux, IECB, Pessac, France;1. Charité – Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institut für Medizinische Genetik und Humangenetik, Berlin, Germany;2. Max Planck Institute for Molecular Genetics, RG Development & Disease, Berlin, Germany;3. Berlin Institute of Health at Charité – Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité Junior Clinician Scientist Program, Berlin, Germany;4. Handsurgery Department, Children’s Hospital Wilhelmstift, Hamburg, Germany;5. Labor Berlin Charité Vivantes GmbH, Department of Human Genetics, Berlin, Germany;6. Max Planck Institute for Molecular Genetics, Human Molecular Genomics Group, Berlin, Germany;7. Institut für Humangenetik Lübeck, Universität zu Lübeck, Lübeck, Germany;8. Department of Medical Genetics, Poznan University of Medical Sciences, Poznan, Poland;9. Centers for Medical Genetics, GENESIS, Poznan, Poland;10. Berlin Institute of Health at Charité – Universitätsmedizin Berlin, BIH Biomedical Innovation Academy, BIH Charité Digital Clinician Scientist Program, Berlin, Germany;1. Amsterdam UMC - AMC, Department of Laboratory Medicine, Laboratory Genetic Metabolic Diseases, Amsterdam, The Netherlands;2. Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, The Netherlands;3. Amsterdam Reproduction & Development, Amsterdam, The Netherlands;4. United for Metabolic Diseases, The Netherlands;5. Department of Pediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General Faculty Hospital, Prague 2, Czech Republic;6. Centre Hospitalier Universitaire de Lyon, CHU Lyon·U 301, Hopital Neurologique, Bron, France;7. Service Biochimie et Biologie Moléculaire Grand Est, UM Pathologies Métaboliques, Erythrocytaires et Dépistage Périnatal, Centre de Biologie et de Pathologie Est, Groupement Hospitalier Est – Hospices Civils de Lyon, Bron Cedex, France;1. Department of Biosciences, University of Milan, via Celoria 26, 20133 Milano, Italy;2. Laboratory of Organic Electronics, Department of Science and Technology, Linköping University, 601 74 Norrköping, Sweden;3. Umeå Plant Science Centre, Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences, 90183 Umeå, Sweden;4. Centro Grandi Strumenti, University of Pavia, via Ferrata 9, 27100 Pavia, Italy;5. Wallenberg Wood Science Center, Department of Science and Technology, Linköping University, Norrköping, Sweden;6. Institute of Biophysics, National Research Council of Italy (CNR), 20133 Milano, Italy;1. Department of Regional Health Research, University of Southern Denmark, Odense, Denmark;2. Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Centre, Dianalund, Denmark;3. Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark;4. Department of Biology, University of Pennsylvania, Philadelphia, PA;5. National Engineering Laboratory for AIDS Vaccine, School of Life Sciences, Jilin University, Changchun, China;6. Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China;7. Amplexa Genetics A/S, Odense, Denmark;8. Department of Genetics, CHU Nantes, Nantes, France;9. University of Nantes, CNRS, INSERM, l''institut du thorax, Nantes, France;10. University of Colorado School of Medicine and Children’s Hospital Colorado, Aurora, CO;11. Institute for Maternal and Child Health, IRCCS “Burlo Garofolo,” Trieste, Italy;12. Department of Neurology, Epileptology Unit, Reference Center for Rare Epilepsies, Sorbonne University, La Pitié-Salpêtrière Hospital, AP-HP, Paris, France;13. Department of Medical Genetics, Pitié-Salpêtrière Hospital, AP-HP, University of Sorbonne, Paris, France;14. GénoPsy, Reference Center for Diagnosis and Management of Genetic Psychiatric Disorders, Vinatier Hospital Center and EDR-Psy Team (National Center for Scientific Research and Lyon 1 Claude Bernard University), Lyon, France;15. iMIND Excellence Center for Autism and Neurodevelopmental Disorders, Lyon, France;16. Department of Medical Genetics, University Hospital of Lyon, Lyon, France |
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| Abstract: | PurposeRPH3A encodes a protein involved in the stabilization of GluN2A subunit of N-methyl-D-aspartate (NMDA)-type glutamate receptors at the cell surface, forming a complex essential for synaptic plasticity and cognition. We investigated the effect of variants in RPH3A in patients with neurodevelopmental disorders.MethodsBy using trio-based exome sequencing, GeneMatcher, and screening of 100,000 Genomes Project data, we identified 6 heterozygous variants in RPH3A. In silico and in vitro models, including rat hippocampal neuronal cultures, have been used to characterize the effect of the variants.ResultsFour cases had a neurodevelopmental disorder with untreatable epileptic seizures [p.(Gln73His)dn; p.(Arg209Lys); p.(Thr450Ser)dn; p.(Gln508His)], and 2 cases [p.(Arg235Ser); p.(Asn618Ser)dn] showed high-functioning autism spectrum disorder. Using neuronal cultures, we demonstrated that p.(Thr450Ser) and p.(Asn618Ser) reduce the synaptic localization of GluN2A; p.(Thr450Ser) also increased the surface levels of GluN2A. Electrophysiological recordings showed increased GluN2A-dependent NMDA ionotropic glutamate receptor currents for both variants and alteration of postsynaptic calcium levels. Finally, expression of the Rph3AThr450Ser variant in neurons affected dendritic spine morphology.ConclusionOverall, we provide evidence that missense gain-of-function variants in RPH3A increase GluN2A-containing NMDA ionotropic glutamate receptors at extrasynaptic sites, altering synaptic function and leading to a clinically variable neurodevelopmental presentation ranging from untreatable epilepsy to autism spectrum disorder. |
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| Keywords: | Epilepsy Excitatory synapse Neurodevelopmental disorder Rabphilin RPH3A |
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