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

Lisa Pavinato, Andrea Delle Vedove, Diana Carli, Marta Ferrero, Silvia Carestiato, Jennifer L. Howe, Emanuele Agolini, Domenico A. Coviello, Ingrid Van De Laar, Ping Yee Billie Au, Eleonora Di Gregorio, Alessandra Fabbiani, Susanna Croci, Maria Antonietta Mencarelli, Lucia P. Bruno, Alessandra Renieri, Danai Veltra, Christalena Sofocleous, Laurence Faivre, Benoit MazelHana Safraou, Anne Sophie DenommCrossed D sign©-Pichon, Marjon A. Van Slegtenhorst, Noor Giesbertz, Richard H. Van Jaarsveld, Anna Childers, R. Curtis Rogers, Antonio Novelli, Silvia De Rubeis, Joseph D. Buxbaum, Stephen W. Scherer, Giovanni Battista Ferrero, Brunhilde Wirth, Alfredo Brusco*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

9 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)534-548
Number of pages15
Issue number2
Publication statusPublished - Feb 2023

Bibliographical note

This research received funding specifically appointed to
Department of Medical Sciences (University of Turin) from the
Italian Ministry for Education, University and Research (Ministero
dell’Istruzione, dell’Università e della Ricerca—MIUR) under the
programme ‘Dipartimenti di Eccellenza 2018–2022’ Project code
D15D18000410001. We thank the support of ‘Associazione Emma
ed Ernesto Rulfo per la Genetica Medica’ and Fondazione Cassa di
Risparmio Torino to A.B. Research to B.W. was supported by the
Deutsche Forschungsgemeinschaft [Wi 945/17-1 (project ID
398410809); Wi 945/18-1 (project ID 384170921); Wi 945/19-1 (project
ID 417989143); SFB1451 (project ID 431549029—A01), and GRK1960
(project ID 233886668)], the European Research Council (ERC) under
the HORIZON EUROPE European Research Council 2020 and
HORIZON EUROPE Marie Sklodowska-Curie Actions 2020 (956185:
SMABEYOND) and Center for Molecular Medicine Cologne (project
no. C18). E.A. and D.C. were supported by Ricerca Corrente 2021,
Ministero della Salute. D.C. was supported by MSALRC21
(Ministero Salute Ricerca Corrente) and ALBURLORF, DLDG514/20
(Progetto Ricerca collaborativo Rete IRCCS IDE). The collection of
some of the samples was supported by the National Institute of
Mental Health NIMH (U01MH111661 to J.D.B.). Two authors of this
publication are members of the European Reference Network for
rare malformation syndromes and rare intellectual and neurodevelopmental disorders, ERN-ITHACA.

Publisher Copyright:
© 2022 The Author(s). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.


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