PTBP1 variants displaying altered nucleocytoplasmic distribution are responsible for a neurodevelopmental disorder with skeletal dysplasia

Polypyrimidine tract-binding protein 1 (PTBP1) is a heterogeneous nuclear ribonucleoprotein primarily known for its alternative splicing activity. It shuttles between the nucleus and cytoplasm via partially overlapping N-terminal nuclear localization (NLS) and export (NES) signals. Despite its fundamental role in cell growth and differentiation, its involvement in human disease remains poorly understood. We identified 27 individuals from 25 families harboring de novo or inherited pathogenic variants - predominantly start-loss (89%) and, to a lesser extent, missense (11%) - affecting NES/NLS motifs. Affected individuals presented with a syndromic neurodevelopmental disorder and variable skeletal dysplasia with disproportionate short stature with short limbs. Intellectual functioning ranged from normal to moderately delayed. Start-loss variants led to translation initiation from an alternative downstream in-frame methionine, resulting in loss of the NES and the first half of the bipartite NLS, and increased cytoplasmic stability. Start-loss and missense variants shared a DNA methylation episignature in peripheral blood and altered nucleocytoplasmic distribution in vitro and in vivo with preferential accumulation in processing bodies, causing aberrant gene expression but normal RNA splicing. Transcriptomic analysis of patient-derived fibroblasts revealed dysregulated pathways involved in osteochondrogenesis and neurodevelopment. Overall, our findings highlight a cytoplasmic role for PTBP1 in RNA stability and disease pathogenesis.

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Publication Details

Journal
Journal of Clinical Investigation
Published
2025-09-18
DOI
https://doi.org/10.1172/jci182100
Citations
2
Primary Topic
Connective tissue disorders research
Type
article
Field-Weighted Citation Impact
3.63
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article

PTBP1 variants displaying altered nucleocytoplasmic distribution are responsible for a neurodevelopmental disorder with skeletal dysplasia

Mari Mori, Arjan Bouman, Michelle L. Thompson, Valérie Cormier‐Daire et al.
2 citations
Journal of Clinical Investigation
Connective tissue disorders research
3.63
article

PTBP1 variants displaying altered nucleocytoplasmic distribution are responsible for a neurodevelopmental disorder with skeletal dysplasia

Mari Mori, Arjan Bouman, Michelle L. Thompson, Valérie Cormier‐Daire, Susan M. Hiatt, Linda Zuurbier, Pauline Terhal, Elizabeth Roeder, Konrad Platzer, Valentin Vautrot, Rebecca O. Littlejohn, Helena Valta, Fulya Taylan, Christel Thauvin‐Robinet, Frédéric Bilan, Frédéric Tran Mau‐Them, Rolph Pfundt, Lynne M. Bird, Lonneke A. M. Aarts, Stephen P. Robertson, Riikka E. Mäkitie, Gemma Poke, Sourav Ghosh, Nina Ekhilevitch, David A. Koolen, Johannes Luppe, Tuula Rinne, Marja W. Wessels, Estelle Colin, Christophe Philippe, Thatjana Gardeitchik, Carlo Marcelis, Dagmar Wieczorek, Patrick Callier, Lisenka E.L.M. Vissers, Jean‐Marc Strub, Ruxandra Bachmann‐Gagescu, Anita M. Rauch, Michael S. Hildebrand, Reem Saadeh‐Haddad, Kristy Lee, Céline Huber, Scott Hickey, Jennifer Kerkhof, Christine Schaeffer‐Reiss, Marco Tartaglia, Céline Pebrel‐Richard, Grace Yoon, David Coman, Michela Ori, Raissa Relator, Julien Paccaud, Christopher T. Gordon, Antonio Vitobello, Andrea Ciolfi, Rinat Zaid, Nathalie Marle, Outi Mäkitie, Angela Tamsin Morgan, Fatima El It, Fanny Laffargue, Bekim Sadiković, Elke de Boer, Marion Aubert‐Mucca, María J. Guillen Sacoto, Laurence Duplomb, Michael A. Levy, David J. Amor, Rana Halloun, Nienke E. Verbeek, Catherine Gooch, Astrid S. Plomp, Jesse M. Hunter, Alice Costantini, Michelle M. Axford, Valentin Bourgeois, Luis A. Pérez‐Jurado, Martin Chevarin, Aymeric Masson, de Man, Marta Sevilla-Porras, Anna Hurst, Quentin Thomas, Françoise Michel, Haley McConkey, Laurence Olivier-Faivre, Yannis Duffourd, Julian Delanne, Sylvie Nguyen, Hana Safraou, Richard Person, Julien Thevenon, Douglas Black, Khaled Osman, Martina Orefice
article en
2 citations

Abstract

Polypyrimidine tract-binding protein 1 (PTBP1) is a heterogeneous nuclear ribonucleoprotein primarily known for its alternative splicing activity. It shuttles between the nucleus and cytoplasm via partially overlapping N-terminal nuclear localization (NLS) and export (NES) signals. Despite its fundamental role in cell growth and differentiation, its involvement in human disease remains poorly understood. We identified 27 individuals from 25 families harboring de novo or inherited pathogenic variants - predominantly start-loss (89%) and, to a lesser extent, missense (11%) - affecting NES/NLS motifs. Affected individuals presented with a syndromic neurodevelopmental disorder and variable skeletal dysplasia with disproportionate short stature with short limbs. Intellectual functioning ranged from normal to moderately delayed. Start-loss variants led to translation initiation from an alternative downstream in-frame methionine, resulting in loss of the NES and the first half of the bipartite NLS, and increased cytoplasmic stability. Start-loss and missense variants shared a DNA methylation episignature in peripheral blood and altered nucleocytoplasmic distribution in vitro and in vivo with preferential accumulation in processing bodies, causing aberrant gene expression but normal RNA splicing. Transcriptomic analysis of patient-derived fibroblasts revealed dysregulated pathways involved in osteochondrogenesis and neurodevelopment. Overall, our findings highlight a cytoplasmic role for PTBP1 in RNA stability and disease pathogenesis.

Journal of Clinical InvestigationVol. 135(22)
University of Pisa (IT), GenVec (US), Western University (CA), Hôpital Necker-Enfants Malades (FR), Centre National de la Recherche Scientifique (FR), Nationwide Children's Hospital (US), Allen Institute for Brain Science (US), Royal Children's Hospital (AU), Karolinska University Hospital (SE), University of Helsinki (FI), Radboud University Nijmegen (NL), Inserm (FR), University of California, Los Angeles (US), The University of Queensland (AU), The University of Melbourne (AU), Université de Bourgogne (FR), Baylor College of Medicine (US), Georgetown University (US), University of Toronto (CA), University of Zurich (CH), Washington University in St. Louis (US), Université Paris Cité (FR), Helsinki University Hospital (FI), Centre Hospitalier Universitaire de Grenoble (FR), London Health Sciences Centre (CA), Wellington Hospital (NZ), Rambam Health Care Campus (IL), Hospital for Sick Children (CA), Erasmus MC (NL), MedStar Georgetown University Hospital (US), Radboud University Medical Center (NL), Karolinska Institutet (SE), University Medical Center Utrecht (NL), University of Alabama at Birmingham (US), Rady Children's Hospital-San Diego (US), Düsseldorf University Hospital (DE), Helsinki Children's Hospital (FI), Assistance Publique – Hôpitaux de Paris (FR), Phoenix (United States) (US), Amphia Ziekenhuis (NL), Amsterdam Neuroscience (NL), Centre Hospitalier Universitaire de Poitiers (FR), Centro de Investigación Biomédica en Red (ES), CHU Dijon Bourgogne (FR), Institut thématique Génétique, génomique et bioinformatique (FR), Institute of Human Genetics (PL), Bambino Gesù Children's Hospital (IT), University Children's Hospital Zurich (CH), Centre Hospitalier Universitaire de Clermont-Ferrand (FR), Hospital Del Mar (ES), Hôpital Purpan (FR), Centre de recherche Translationnelle en Médecine moléculaire (FR), Caris Life Sciences (United States) (US), Institute of Genetics (CA), HudsonAlpha Institute for Biotechnology (US), Pediatrics and Genetics (US), Murdoch Children's Research Institute (AU), Institute of Genetics (HU), Austin Health (AU), Institut des Maladies Génétiques Imagine (FR), Folkhälsans Forskningscentrum (FI), Children's Health Queensland Hospital and Health Service (AU), Université Bourgogne Europe (FR), Heinrich Heine University Düsseldorf (DE), Université d'Angers (FR), The Ohio State University (US), Université de Strasbourg (FR), University of Otago (NZ), University of Amsterdam (NL), Université Grenoble Alpes (FR), Leipzig University (DE)
Openalex Percentile: Top 7%
Connective tissue disorders research
3.63
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