PubMed · 42749777
De novo variants in the poly(rC)-binding protein gene PCBP1 cause a neurodevelopmental disorder.
Abstract
Poly(rC)-binding protein 1 (PCBP1), a splicing factor and key member of the hnRNP E family, was initially characterized for its tumor suppressive properties. More recently, its role in gene regulation in the brain and nervous system has attracted growing interest. Through an international multicenter collaboration, we identified 16 de novo pathogenic variants in PCBP1 across 17 subjects from 16 unrelated families. All affected individuals exhibited intellectual disability (ID), with autism spectrum disorder (ASD) as a prominent feature. Functional analysis in primary hippocampal mouse neuron cultures indicated that PCBP1 variants impair dendritic arborization, underscoring their deleterious effects. Transcriptomic profiling by RNA sequencing of subject-derived T cells showed a distinctive signature characterized by significantly increased exon skipping. These results highlight the contribution of PCBP1 in neurogenesis and neuritogenesis, which is impacted by loss-of-function variants expressed in neuronal cells, thereby supporting the link between splicing defects and neurodevelopmental disorders. Collectively, our findings demonstrate the prominent role of PCBP1 in neurodevelopment, reaffirming the importance of splicing regulation in mammalian neurodevelopment.
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Wallid Deb, Thomas Besnard, Florence Desprez, Benjamin Cogné, Laura Do Souto Ferreira, Virginie Vignard, Sylviane Marouillat, Louis Januel, Svetlana Gorokhova, Tiffany Busa, Victor Morel, Benjamin Dauriat, Vincent Des Portes, Eyyüp Üçtepe, Özlem Akgün Doğan, Ahmet Yeşilyurt, Yasemin Alanay, Anne M Slavotinek, Yu An, Hane Lee, Jessy Hary, Peter Kannu, Taryn B Athey, Ingrid M B H van de Laar, Marjon A van Slegtenhorst, Patricia Dickson, Rachel Slaugh, Fadi F Hamdan, Jean-François Soucy, Jacques L Michaud, Alison M Muir, Rebecca Buchert, Tobias B Haack, Dominic Imort, Sérgio B Sousa, Belinda Campos-Xavier, Pedro M Almeida, Borut Peterlin, Sophie Kaspar, Christian Netzer, Hans Zempel, Meghan C Towne, Roger L Ladda, Susan L Sell, Lina Quteineh, Romane Meurs, Stylianos E Antonarakis, Pawel Gawlinski, Xiaofei Song, Wojciech Wiszniewski, Daniel G Calame, Jennifer E Posey, Frederic Ebstein, James R Lupski, Bertrand Isidor, Stéphane Bézieau, Frédéric Laumonnier, Sébastien Küry. 2026-09-16. De novo variants in the poly(rC)-binding protein gene PCBP1 cause a neurodevelopmental disorder.. https://doi.org/10.1038/s41380-026-03877-w
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