- Identification of 16 de novo pathogenic PCBP1 variants in 17 individuals from 16 families causing intellectual disability with prominent autism spectrum disorder.
- Functional studies in primary hippocampal mouse neurons show PCBP1 variants impair dendritic arborisation, indicating deleterious effects on neuritogenesis.
- RNA sequencing of subject-derived T cells reveals a distinct transcriptomic signature with significantly increased exon skipping, linking splicing defects to neurodevelopmental disorder.
Mol Psychiatry. 2026 Sep 16. doi: 10.1038/s41380-026-03877-w. Online ahead of print.
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.
PMID:42749777 | DOI:10.1038/s41380-026-03877-w
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