Functional analysis across model systems implicates ribosomal proteins in growth and proliferation defects associated with hypoplastic left heart syndrome
Hypoplastic left heart syndrome (HLHS) is the most lethal congenital heart disease (CHD) whose genetic basis remains elusive, likely due to oligogenic complexity. To identify regulators of cardiomyocyte (CM) proliferation relevant to HLHS, we performed a genome-wide siRNA screen in human iPSC-derived CMs, revealing ribosomal protein (RP) genes as the most prominent effectors of CM proliferation. Whole-genome sequencing of 25 HLHS proband-parent trios similarly showed enrichment of rare RP gene variants, including a damaging RPS15A promoter variant shared in a familial CHD case. Cross-species functional analyses demonstrated that perturbation of RP genes impairs cardiac growth: knockdown of RPS15A, RPS17, RPL26L1, RPL39, or RPS15 reduced CM proliferation, caused cardiac malformations in <i>Drosophila</i>, and produced hypoplastic or dysfunctional hearts in zebrafish. Genetic interactions between RP genes and key cardiac transcription factors (TBX5 and NKX2-7) further support their developmental role. Importantly, p53 suppression or Hippo activation partially rescued RP deficiency phenotypes. Together, these findings implicate RP genes as critical regulators of cardiogenesis and candidate contributors to HLHS.
Authors
- Xin-Xin I. Zeng (ORCID: https://orcid.org/0000-0002-2707-7759)
- Jeanne L. Theis (ORCID: https://orcid.org/0000-0002-4494-8683)
- Stanley M. Walls (ORCID: https://orcid.org/0000-0002-5202-9927)
- Analyne Schroeder (ORCID: https://orcid.org/0000-0002-7537-458X)
- Maria A Missinato (ORCID: https://orcid.org/0000-0001-9055-758X)
- Greg Duester
- Tanja Nielsen (ORCID: https://orcid.org/0000-0002-2389-7514)
- Katja Birker (ORCID: https://orcid.org/0000-0003-4789-0971)
- Timothy M. Olson (ORCID: https://orcid.org/0000-0003-2716-9423)
- James Marchant (ORCID: https://orcid.org/0000-0002-9551-835X)
- Alexandre R. Colas (ORCID: https://orcid.org/0000-0001-8489-0570)
- Anaïs Kervadec (ORCID: https://orcid.org/0000-0001-8105-6871)
- Timothy J. Nelson (ORCID: https://orcid.org/0000-0002-3862-7023)
- Karen Ocorr (ORCID: https://orcid.org/0000-0003-2593-0119)
- Georg Vogler (ORCID: https://orcid.org/0000-0002-8303-3531)
- Manuel Vázquez Romero
- Rolf Bodmer (ORCID: https://orcid.org/0000-0001-9087-1210)
- Marie Berenguer (ORCID: https://orcid.org/0000-0002-3629-9505)
- Aashna Lamba
- Katya Marchetti (ORCID: https://orcid.org/0009-0000-9635-3246)
Institutions
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Discovery Institute (US)
- WinnMed (US)
- University of California San Diego (US)
- Mayo Clinic in Arizona (US)
- Freie Universität Berlin (DE)
Publication Details
- Journal
- eLife
- Published
- 2025-05-22
- DOI
- https://doi.org/10.7554/elife.106231
- Primary Topic
- RNA and protein synthesis mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Institutes of Health