The Journal of clinical investigation · 2025

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

СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди

Обработка статьи · этапы, ошибки и управление

Загрузка состояния…

История · было → стало

Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.

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

Аннотация

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.

Предметные рубрики MeSH

Humans Polypyrimidine Tract-Binding Protein Heterogeneous-Nuclear Ribonucleoproteins Female Male Neurodevelopmental Disorders Child Cell Nucleus Osteochondrodysplasias Cytoplasm Adolescent Mutation, Missense Child, Preschool Adult Nuclear Localization Signals Alternative Splicing

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

Ошибки и ограничения

Аннотация

Предметные рубрики MeSH