Missense variants in RPH3A cause defects in excitatory synaptic function and are associated with a clinically variable neurodevelopmental disorder.

Autor:	Pavinato L; Department of Medical Sciences, University of Turin, Turin, Italy; Institute of Oncology Research (IOR), Bellinzona, Switzerland; Università della Svizzera Italiana, Lugano, Switzerland., Stanic J; Department of Pharmacological and Biomolecular Sciences, DiSFeB, University of the Studies of Milan, Milan, Italy., Barzasi M; Department of Pharmacological and Biomolecular Sciences, DiSFeB, University of the Studies of Milan, Milan, Italy., Gurgone A; Department of Neuroscience, University of Turin, Turin, Italy., Chiantia G; Department of Neuroscience, University of Turin, Turin, Italy., Cipriani V; William Harvey Research Institute, Clinical Pharmacology Precision Medicine, Queen Mary University of London, Charterhouse Square, United Kingdom., Eberini I; Department of Pharmacological and Biomolecular Sciences, DiSFeB, University of the Studies of Milan, Milan, Italy., Palazzolo L; Department of Pharmacological and Biomolecular Sciences, DiSFeB, University of the Studies of Milan, Milan, Italy., Di Luca M; Department of Pharmacological and Biomolecular Sciences, DiSFeB, University of the Studies of Milan, Milan, Italy., Costa A; Department of Biosciences, University of the Studies of Milan, Milan, Italy; Institute of Biophysics, Consiglio Nazionale delle Ricerche (CNR), Milan, Italy., Marcantoni A; Department of Drug Science and Technology, University of Turin, Turin, Italy., Biamino E; Department of Pediatrics, Regina Margherita Children Hospital, Turin, Italy., Spada M; Department of Pediatrics, Regina Margherita Children Hospital, Turin, Italy., Hiatt SM; HudsonAlpha Institute for Biotechnology, Huntsville, AL., Kelley WV; HudsonAlpha Institute for Biotechnology, Huntsville, AL., Vestito L; William Harvey Research Institute, Clinical Pharmacology Precision Medicine, Queen Mary University of London, Charterhouse Square, United Kingdom., Sisodiya SM; Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, United Kingdom; Chalfont Centre for Epilepsy Bucks, Chalfont St Peter, United Kingdom., Efthymiou S; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, London, United Kingdom., Chand P; Department of Paediatric and Child Health, Aga Khan University Hospital, Karachi, Pakistan., Kaiyrzhanov R; University College London, UCL Queen Square Institute of Neurology, London, United Kingdom., Bruselles A; Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy., Cardaropoli S; Department of Public Health and Pediatric Sciences, University of Torino, Torino, Italy., Tartaglia M; Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy., De Rubeis S; Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY., Buxbaum JD; Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY., Smedley D; William Harvey Research Institute, Clinical Pharmacology Precision Medicine, Queen Mary University of London, Charterhouse Square, United Kingdom., Ferrero GB; Department of Clinical and Biological Sciences, University of Turin, Orbassano, TO, Italy., Giustetto M; Department of Neuroscience, University of Turin, Turin, Italy., Gardoni F; Department of Pharmacological and Biomolecular Sciences, DiSFeB, University of the Studies of Milan, Milan, Italy., Brusco A; Department of Medical Sciences, University of Turin, Turin, Italy; Medical Genetics Unit, Città della Salute e della Scienza University Hospital, Turin, Italy. Electronic address: alfredo.brusco@unito.it.
Jazyk:	angličtina
Zdroj:	Genetics in medicine : official journal of the American College of Medical Genetics [Genet Med] 2023 Nov; Vol. 25 (11), pp. 100922. Date of Electronic Publication: 2023 Jul 01.
DOI:	10.1016/j.gim.2023.100922
Abstrakt:	Purpose: RPH3A 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. Methods: By 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. Results: Four 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 Rph3A Thr450Ser variant in neurons affected dendritic spine morphology. Conclusion: Overall, 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. Competing Interests: Conflict of Interest The authors declare no conflicts of interest. (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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