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Updated: Jan 7, 2026
Author Spotlight: Effect of Left Atrial Ligation on Avian Embryonic Hearts and HLHS Implications
Published on: June 16, 2023
Functional analysis across model systems implicates ribosomal proteins in growth and proliferation defects associated
Tanja Nielsen1,2, Anaïs Kervadec1, Jeanne L Theis3
1Center for Cardiovascular and Muscular Diseases, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, United States.
Insights
Ribosomal protein genes are key regulators of heart development and may contribute to hypoplastic left heart syndrome (HLHS). This study identified these genes as crucial for cardiomyocyte proliferation and cardiac growth.
Area of Science:
- Cardiovascular Biology
- Genetics
- Developmental Biology
Background:
- Hypoplastic left heart syndrome (HLHS) is a severe congenital heart defect with an unknown genetic cause, possibly due to complex genetic factors.
- Identifying genes that regulate cardiomyocyte proliferation is crucial for understanding HLHS pathogenesis.
Purpose of the Study:
- To identify novel regulators of cardiomyocyte proliferation relevant to HLHS.
- To investigate the role of ribosomal protein (RP) genes in cardiac development and HLHS.
Main Methods:
- Genome-wide siRNA screen in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs).
- Whole-genome sequencing in HLHS patient-parent trios.
- Cross-species functional analyses in *Drosophila* and zebrafish.
- Investigated genetic interactions with cardiac transcription factors and modulation of p53/Hippo pathways.
Main Results:
- Ribosomal protein (RP) genes were identified as major regulators of cardiomyocyte proliferation.
- Rare RP gene variants were enriched in HLHS patients, including a damaging RPS15A variant in a familial case.
- Perturbation of RP genes impaired cardiac growth across species, causing reduced proliferation and heart malformations.
- RP genes interact with cardiac transcription factors (TBX5, NKX2-7) and their deficiency phenotypes can be partially rescued by p53 suppression or Hippo activation.
Conclusions:
- RP genes are critical regulators of cardiogenesis and are implicated as candidate genes contributing to HLHS.
- These findings highlight a novel genetic pathway involved in congenital heart disease development.
Abstract:
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 Drosophila, 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.
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