CAPRIN1 haploinsufficiency causes a neurodevelopmental disorder with language impairment, ADHD and ASD.

Autor:	Pavinato L; Department of Medical Sciences, University of Turin, 10126 Turin, Italy.; Institute of Human Genetics, Center for Molecular Medicine Cologne, Center for Rare Diseases Cologne, University Hospital Cologne, University of Cologne, 50931 Cologne, Germany., Delle Vedove A; Institute of Human Genetics, Center for Molecular Medicine Cologne, Center for Rare Diseases Cologne, University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.; Institute for Genetics, University of Cologne, 50674 Cologne, Germany., Carli D; Department of Public Health and Pediatrics, University of Turin, 10126 Turin, Italy.; Pediatric Onco-Hematology, Stem Cell Transplantation and Cell Therapy Division, Regina Margherita Children's Hospital, Città Della Salute e Della Scienza di Torino, 10126 Turin, Italy., Ferrero M; Department of Medical Sciences, University of Turin, 10126 Turin, Italy.; Experimental Zooprophylactic Institute of Piedmont, Liguria e Valle d'Aosta, 10154 Turin, Italy., Carestiato S; Department of Medical Sciences, University of Turin, 10126 Turin, Italy., Howe JL; The Centre for Applied Genomics, Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada., Agolini E; Laboratory of Medical Genetics, IRCCS, Ospedale Pediatrico Bambino Gesù, Rome, Italy., Coviello DA; Laboratory of Human Genetics, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy., van de Laar I; Clinical Genetics, Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, 3015 CN, Rotterdam, The Netherlands., Au PYB; Department of Medical Genetics, Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB T2N 1N4, Canada., Di Gregorio E; Medical Genetics Unit, Città della Salute e della Scienza University Hospital, 10126 Turin, Italy., Fabbiani A; Medical Genetics Unit, Azienda Ospedaliera Universitaria Senese, 53100 Siena, Italy.; Medical Genetics, University of Siena, 53100 Siena, Italy.; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy., Croci S; Medical Genetics, University of Siena, 53100 Siena, Italy.; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy., Mencarelli MA; Medical Genetics Unit, Azienda Ospedaliera Universitaria Senese, 53100 Siena, Italy., Bruno LP; Medical Genetics, University of Siena, 53100 Siena, Italy.; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy., Renieri A; Medical Genetics Unit, Azienda Ospedaliera Universitaria Senese, 53100 Siena, Italy.; Medical Genetics, University of Siena, 53100 Siena, Italy.; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy., Veltra D; Laboratory of Medical Genetics, School of Medicine, National & Kapodistrian University of Athens, 'Aghia Sophia' Children's Hospital, 11527 Athens, Greece., Sofocleous C; Laboratory of Medical Genetics, School of Medicine, National & Kapodistrian University of Athens, 'Aghia Sophia' Children's Hospital, 11527 Athens, Greece., Faivre L; Centre de référence Anomalies du Développement et Syndromes Malformatifs, Fédération Hospitalo-Universitaire TRANSLAD, CHU Dijon, 21079 Dijon, France.; UMR1231 GAD, Inserm-Université Bourgogne-Franche Comté, 21078 Dijon, France., Mazel B; Centre de référence Anomalies du Développement et Syndromes Malformatifs, Fédération Hospitalo-Universitaire TRANSLAD, CHU Dijon, 21079 Dijon, France., Safraou H; UMR1231 GAD, Inserm-Université Bourgogne-Franche Comté, 21078 Dijon, France.; Unité Fonctionnelle Innovation en Diagnostic génomique des maladies rares, FHU TRANSLAD, CHU Dijon Bourgogne, 21000 Dijon, France., Denommé-Pichon AS; UMR1231 GAD, Inserm-Université Bourgogne-Franche Comté, 21078 Dijon, France.; Unité Fonctionnelle Innovation en Diagnostic génomique des maladies rares, FHU TRANSLAD, CHU Dijon Bourgogne, 21000 Dijon, France., van Slegtenhorst MA; Clinical Genetics, Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, 3015 CN, Rotterdam, The Netherlands., Giesbertz N; Department of Genetics, University Medical Centre Utrecht, 3584 CX, Utrecht, The Netherlands., van Jaarsveld RH; Department of Genetics, University Medical Centre Utrecht, 3584 CX, Utrecht, The Netherlands., Childers A; Greenwood Genetic Center, Greenville, SC 29646, USA., Rogers RC; Greenwood Genetic Center, Greenville, SC 29646, USA., Novelli A; Laboratory of Medical Genetics, IRCCS, Ospedale Pediatrico Bambino Gesù, Rome, Italy., De Rubeis S; Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.; Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Buxbaum JD; Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.; The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.; Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA., Scherer SW; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.; McLaughlin Centre, University of Toronto, Toronto, ON M5S 1A1, Canada., Ferrero GB; Department of Clinical and Biological Sciences, University of Turin, 10149 Orbassano, TO, Italy., Wirth B; Institute of Human Genetics, Center for Molecular Medicine Cologne, Center for Rare Diseases Cologne, University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.; Institute for Genetics, University of Cologne, 50674 Cologne, Germany., Brusco A; Department of Medical Sciences, University of Turin, 10126 Turin, Italy.; Medical Genetics Unit, Città della Salute e della Scienza University Hospital, 10126 Turin, Italy.
Jazyk:	angličtina
Zdroj:	Brain : a journal of neurology [Brain] 2023 Feb 13; Vol. 146 (2), pp. 534-548.
DOI:	10.1093/brain/awac278
Abstrakt:	We describe an autosomal dominant disorder associated with loss-of-function variants in the Cell cycle associated protein 1 (CAPRIN1; MIM*601178). CAPRIN1 encodes a ubiquitous protein that regulates the transport and translation of neuronal mRNAs critical for synaptic plasticity, as well as mRNAs encoding proteins important for cell proliferation and migration in multiple cell types. We identified 12 cases with loss-of-function CAPRIN1 variants, and a neurodevelopmental phenotype characterized by language impairment/speech delay (100%), intellectual disability (83%), attention deficit hyperactivity disorder (82%) and autism spectrum disorder (67%). Affected individuals also had respiratory problems (50%), limb/skeletal anomalies (50%), developmental delay (42%) feeding difficulties (33%), seizures (33%) and ophthalmologic problems (33%). In patient-derived lymphoblasts and fibroblasts, we showed a monoallelic expression of the wild-type allele, and a reduction of the transcript and protein compatible with a half dose. To further study pathogenic mechanisms, we generated sCAPRIN1+/- human induced pluripotent stem cells via CRISPR-Cas9 mutagenesis and differentiated them into neuronal progenitor cells and cortical neurons. CAPRIN1 loss caused reduced neuronal processes, overall disruption of the neuronal organization and an increased neuronal degeneration. We also observed an alteration of mRNA translation in CAPRIN1+/- neurons, compatible with its suggested function as translational inhibitor. CAPRIN1+/- neurons also showed an impaired calcium signalling and increased oxidative stress, two mechanisms that may directly affect neuronal networks development, maintenance and function. According to what was previously observed in the mouse model, measurements of activity in CAPRIN1+/- neurons via micro-electrode arrays indicated lower spike rates and bursts, with an overall reduced activity. In conclusion, we demonstrate that CAPRIN1 haploinsufficiency causes a novel autosomal dominant neurodevelopmental disorder and identify morphological and functional alterations associated with this disorder in human neuronal models. (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
Databáze:	MEDLINE
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