Complete genetic knockout of PRRC2B — an RNA-binding protein governing uORF-dependent and independent translation initiation — produces patent ductus arteriosus (PDA) and neonatal lethality in mice, while a congenital heart disease-mimicking knock-in mutation that preserves the truncated ΔE16 isoform causes no structural cardiac defect. Integrated proteomics, translatomics, and polysome-sequencing in embryonic mouse hearts (E18.5) reveal that PRRC2B loss broadly suppresses smooth muscle-specific gene translation, reduces smooth muscle cell numbers confirmed by flow cytometry, and impairs proliferation, migration, and contractile gene expression in human aortic smooth muscle cells under lentiviral shRNA knockdown.
PDA affects roughly 1 in 2,000 full-term births and is far more prevalent in premature infants, yet its molecular drivers remain incompletely mapped. Placing PRRC2B within translational — not merely transcriptional — control of smooth muscle fate adds a mechanistic layer largely unexplored in congenital cardiovascular biology. The isoform dissection is particularly compelling: it suggests therapeutic strategies might selectively restore full-length PRRC2B without disrupting ΔE16 function. Limitations are substantial, however. All structural phenotypes are murine; human genetic validation beyond the single mutation-mimicking knock-in is absent. Cell-line experiments use HEK293T, a non-cardiac model. Causality in humans remains unestablished. As a preprint posted on medRxiv and not yet peer-reviewed, findings should be interpreted cautiously — analytical choices in dual-omics integration warrant independent scrutiny. Overall, this is a mechanistically rich, incrementally paradigm-shifting contribution to congenital heart disease biology.