{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T19:21:22Z","timestamp":1790018482145,"version":"4.0.1"},"reference-count":77,"publisher":"American Society for Clinical Investigation","issue":"22","license":[{"start":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T00:00:00Z","timestamp":1763337600000},"content-version":"vor","delay-in-days":60,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"PIA ANR","award":["ISITE-BFC"],"award-info":[{"award-number":["ISITE-BFC"]}]},{"DOI":"10.13039\/501100000780","name":"European Union","doi-asserted-by":"crossref","award":["FEDER"],"award-info":[{"award-number":["FEDER"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"crossref","award":["PNRR-MR1-2022-12376811"],"award-info":[{"award-number":["PNRR-MR1-2022-12376811"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Italian Ministry of University and Research","award":["FOE 2020"],"award-info":[{"award-number":["FOE 2020"]}]},{"name":"European Union\u2019s Horizon 2020","award":["779257"],"award-info":[{"award-number":["779257"]}]},{"name":"Genome Canada and the Ontario Genomics Institute","award":["OGI-188"],"award-info":[{"award-number":["OGI-188"]}]},{"name":"French Investments for the Future Programme","award":["A210019MS"],"award-info":[{"award-number":["A210019MS"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,11,17]]},"abstract":"<jats:p>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 \u2014 predominantly start-loss (89%) and, to a lesser extent, missense (11%) \u2014 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.<\/jats:p>","DOI":"10.1172\/jci182100","type":"journal-article","created":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T16:00:11Z","timestamp":1758211211000},"source":"Crossref","is-referenced-by-count":7,"title":["PTBP1 variants displaying altered nucleocytoplasmic distribution are responsible for a neurodevelopmental disorder with skeletal dysplasia"],"prefix":"10.1172","volume":"135","author":[{"given":"Aymeric","family":"Masson","sequence":"first","affiliation":[{"name":"Universit\u00e9 Bourgogne Europe, CHU Dijon Bourgogne, Centre de recherche Translationnelle en M\u00e9decine mol\u00e9culaire \u2013 Inserm UMR1231 \u00e9quipe GAD, Dijon, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julien","family":"Paccaud","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Bourgogne Europe, CHU Dijon Bourgogne, Centre de recherche Translationnelle 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Helsinki, Finland."},{"name":"Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden."},{"name":"Clinical Genetics and Genomics, Karolinska University Hospital, Solna, Sweden."},{"name":"Folkh\u00e4lsan Institute of Genetics, Helsinki, Finland."},{"name":"Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Val\u00e9rie","family":"Cormier-Daire","sequence":"additional","affiliation":[{"name":"INSERM UMR1163, Imagine Institute, Paris Cit\u00e9 University, Paris, France."},{"name":"Service de m\u00e9decine g\u00e9nomique des maladies rares, Centre de r\u00e9f\u00e9rence pour les maladies osseuses constitutionnelles, AP-HP, H\u00f4pital Necker-Enfants Malades, Paris, F-75015, 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