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A novel RNA-binding protein,\n                  <jats:underline>Pr<\/jats:underline>\n                  o-rich\n                  <jats:underline>C<\/jats:underline>\n                  oiled- coil Containing Protein\n                  <jats:underline>2B<\/jats:underline>\n                  (PRRC2B), has been shown to mediate both upstream (u)ORF- dependent and independent regulation of translation initiation, which is essential for cell cycle progression and proliferation. We identified two alternative spliced isoforms of\n                  <jats:italic>PRRC2B<\/jats:italic>\n                  mRNA in human and mouse hearts, as well as in multiple cell types: the full-length and the exon 16- excluded isoform \u0394E16. A congenital heart disease-associated human mutation-mimicking knock- in of the equivalent variant in the mouse genome results in the depletion of full-length\n                  <jats:italic>Prrc2b<\/jats:italic>\n                  mRNA, but not the alternative spliced truncated form \u0394E16. This mouse model does not cause any apparent structural or functional cardiac disorders. In contrast, global genetic inactivation of the\n                  <jats:italic>Prrc2b<\/jats:italic>\n                  gene in the mouse genome, nullifying both mRNA isoforms, caused patent ductus arteriosus (PDA) and neonatal lethality. Bulk and single-nucleus transcriptome profiling analyses of embryonic mouse hearts at E18.5 demonstrate a significant overall downregulation of multiple smooth muscle-specific genes in\n                  <jats:italic>Prrc2b<\/jats:italic>\n                  knockout mice, likely due to a reduced smooth muscle cell number as confirmed by flow cytometry. An integrated dual-omics analysis of proteomic and translatomic changes in\n                  <jats:italic>Prrc2b<\/jats:italic>\n                  null mouse E18.5 embryonic hearts, combined with polysome- seq and RNA-seq in HEK293T cells, reveals enrichment of PRRC2B-regulated target mRNAs encoding essential factors required for cell proliferation and cardiovascular development. Lentiviral-shRNA-mediated knockdown of PRRC2B in human aorta-derived smooth muscle cells (HASMCs) reduces the proliferation, migration, and contractile function-related gene expression. Overall, this study demonstrates the functional and mechanistic connections between PRRC2B- mediated translational control and congenital cardiovascular development and disorders.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Discovery bullet points<\/jats:title>\n                  <jats:p>1. PRRC2B has two alternative splicing isoforms, full-length and exon 16-skipped (\u0394E16) mRNAs in humans and mice, with redundant and specialized interactome and likely functions.<\/jats:p>\n                  <jats:p>\n                    2. Full-length\n                    <jats:italic>Prrc2b<\/jats:italic>\n                    knockout mice exhibit no apparent cardiac phenotypes, whereas the double knockout of both isoforms results in patent ductus arteriosus and neonatal lethality in mice.\n                  <\/jats:p>\n                  <jats:p>\n                    3. Multi-omics analyses of\n                    <jats:italic>Prrc2b<\/jats:italic>\n                    dual-isoform knockout mice reveal translation dysregulation of specific proteins in embryonic hearts and a decrease in smooth muscle cell abundance.\n                  <\/jats:p>\n                  <jats:p>4. PRRC2B knockdown in human aorta-derived smooth muscle cells compromises cell proliferation, migration, and contractile gene expression.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.09.26.24313895","type":"posted-content","created":{"date-parts":[[2024,9,27]],"date-time":"2024-09-27T15:55:17Z","timestamp":1727452517000},"source":"Crossref","is-referenced-by-count":1,"title":["Loss-of-function of RNA-binding protein PRRC2B causes translational defects and cardiovascular malformation"],"prefix":"10.64898","author":[{"given":"Debojyoti","family":"Das","sequence":"first","affiliation":[{"name":"Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of Medicine & Dentistry, Rochester, NY 14642"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksandr V.","family":"Ivanov","sequence":"additional","affiliation":[{"name":"Aab Cardiovascular Research Institute, Department of Medicine, University of Rochester School of 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