Disrupted PQBP1-HNRNPU-LINE-1 axis underlies aberrant neurodevelopment in renpenning syndrome.

Abstract

Mutations in RNA splicing factor PQBP1 cause Renpenning syndrome (RS), yet whether LINE-1 (L1) contributes to RS pathogenesis remains unclear. Here, we generated human forebrain organoids model carrying a novel patient-derived PQBP1 variant (c.28 C > G; p.R10G), and observed impaired neurogenesis in RS organoids. Bulk and single-cell RNA-sequencing revealed that PQBP1 R10G mutation upregulated evolutionarily ancient L1 expression and induced aberrant L1 splicing, resulting in the redundant production of non-canonical L1-containing transcripts. Mechanistically, disrupted PQBP1-HNRNPU interaction by PQBP1 R10G mutation impaired U1/U2 small nuclear ribonucleoprotein (snRNP) recruitment to splicing sites, leading to increased L1-containing intron retention of neurodevelopmental genes, including WDR11. L1 retention reduced canonical WDR11 transcripts and consequently protein expression. Canonical WDR11, not L1-containing isoform, ameliorated the neurodevelopmental deficits of RS organoids. Together, our findings establish the dysregulated PQBP1-HNRNPU-L1 axis as a pathogenic driver of RS and nominate WDR11 as a potential therapeutic target for RS.