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 regulating gene expression in the brain and nervous system has attracted growing interest. Through an international multicenter collaboration, we identified 13 de novo pathogenic variants in PCBP1 across 13 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 demonstrated that PCBP1 variants impair dendritic arborization, underscoring their deleterious effects. Transcriptomic profiling by RNA sequencing of subjects-derived T cells showed a distinctive signature characterized by significantly increased exon skipping. These results highlight the essential role of PCBP1 in neurogenesis and neuritogenesis, revealing the impact of loss-of-function variants in cells harboring PCBP1 pathogenic variants, thereby confirming the link between splicing defects and neurodevelopmental disorders. Collectively, our findings demonstrate the critical role of PCBP1 in neurodevelopment, reaffirming the importance of splicing regulation in mammalian neurodevelopment.