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

  • Brain. 2023 Feb 13;146(2):534-548. doi: 10.1093/brain/awac278.
Lisa Pavinato  1  2 ,  Andrea Delle Vedove  2  3 ,  Diana Carli  4  5 ,  Marta Ferrero  1  6 ,  Silvia Carestiato  1 ,  Jennifer L Howe  7 ,  Emanuele Agolini  8 ,  Domenico A Coviello  9 ,  Ingrid van de Laar  10 ,  Ping Yee Billie Au  11 ,  Eleonora Di Gregorio  12 ,  Alessandra Fabbiani  13  14  15 ,  Susanna Croci  14  15 ,  Maria Antonietta Mencarelli  13 ,  Lucia P Bruno  14  15 ,  Alessandra Renieri  13  14  15 ,  Danai Veltra  16 ,  Christalena Sofocleous  16 ,  Laurence Faivre  17  18 ,  Benoit Mazel  17 ,  Hana Safraou  18  19 ,  Anne-Sophie Denommé-Pichon  18  19 ,  Marjon A van Slegtenhorst  10 ,  Noor Giesbertz  20 ,  Richard H van Jaarsveld  20 ,  Anna Childers  21 ,  R Curtis Rogers  21 ,  Antonio Novelli  8 ,  Silvia De Rubeis  22  23  24  25 ,  Joseph D Buxbaum  22  23  24  26 ,  Stephen W Scherer  27  28 ,  Giovanni Battista Ferrero  29 ,  Brunhilde Wirth  2  3 ,  Alfredo Brusco  1  12
Affiliations
  • 1. Department of Medical Sciences, University of Turin, 10126 Turin, Italy.
  • 2. Institute of Human Genetics, Center for Molecular Medicine Cologne, Center for Rare Diseases Cologne, University Hospital Cologne, University of Cologne, 50931 Cologne, Germany.
  • 3. Institute for Genetics, University of Cologne, 50674 Cologne, Germany.
  • 4. Department of Public Health and Pediatrics, University of Turin, 10126 Turin, Italy.
  • 5. 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.
  • 6. Experimental Zooprophylactic Institute of Piedmont, Liguria e Valle d'Aosta, 10154 Turin, Italy.
  • 7. The Centre for Applied Genomics, Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada.
  • 8. Laboratory of Medical Genetics, IRCCS, Ospedale Pediatrico Bambino Gesù, Rome, Italy.
  • 9. Laboratory of Human Genetics, IRCCS Istituto Giannina Gaslini, 16147 Genoa, Italy.
  • 10. Clinical Genetics, Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, 3015 CN, Rotterdam, The Netherlands.
  • 11. Department of Medical Genetics, Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB T2N 1N4, Canada.
  • 12. Medical Genetics Unit, Città della Salute e della Scienza University Hospital, 10126 Turin, Italy.
  • 13. Medical Genetics Unit, Azienda Ospedaliera Universitaria Senese, 53100 Siena, Italy.
  • 14. Medical Genetics, University of Siena, 53100 Siena, Italy.
  • 15. Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy.
  • 16. Laboratory of Medical Genetics, School of Medicine, National & Kapodistrian University of Athens, 'Aghia Sophia' Children's Hospital, 11527 Athens, Greece.
  • 17. Centre de référence Anomalies du Développement et Syndromes Malformatifs, Fédération Hospitalo-Universitaire TRANSLAD, CHU Dijon, 21079 Dijon, France.
  • 18. UMR1231 GAD, Inserm-Université Bourgogne-Franche Comté, 21078 Dijon, France.
  • 19. Unité Fonctionnelle Innovation en Diagnostic génomique des maladies rares, FHU TRANSLAD, CHU Dijon Bourgogne, 21000 Dijon, France.
  • 20. Department of Genetics, University Medical Centre Utrecht, 3584 CX, Utrecht, The Netherlands.
  • 21. Greenwood Genetic Center, Greenville, SC 29646, USA.
  • 22. Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • 23. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • 24. The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • 25. Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • 26. Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • 27. Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
  • 28. McLaughlin Centre, University of Toronto, Toronto, ON M5S 1A1, Canada.
  • 29. Department of Clinical and Biological Sciences, University of Turin, 10149 Orbassano, TO, Italy.
PMID: 35979925 DOI: 10.1093/brain/awac278
Abstract

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.

Keywords
ADHD; ASD; CAPRIN1; RNG105; neurodevelopment.