PUBLICATION
Functional analysis across model systems implicates ribosomal proteins in growth and proliferation defects associated with hypoplastic left heart syndrome
- Authors
- Nielsen, T., Kervadec, A., Theis, J.L., Missinato, M.A., Marchant, J., Romero, M., Marchetti, K., Lamba, A., Zeng, X.I., Berenguer, M., Walls, S.M., Schroeder, A., Birker, K., Duester, G., Grossfeld, P., Nelson, T.J., Olson, T.M., Ocorr, K., Bodmer, R., Vogler, G., Colas, A.R.
- ID
- ZDB-PUB-251212-2
- Date
- 2025
- Source
- eLIFE 14: (Journal)
- Registered Authors
- Berenguer, Marie
- Keywords
- Drosophila, HLHS, congenital heart disease, genetics, genomics, hiPSCs, human, ribosomal poteins, zebrafish
- MeSH Terms
-
- Animals
- Cell Proliferation*/genetics
- Disease Models, Animal
- Drosophila
- Humans
- Hypoplastic Left Heart Syndrome*/genetics
- Hypoplastic Left Heart Syndrome*/pathology
- Hypoplastic Left Heart Syndrome*/physiopathology
- Induced Pluripotent Stem Cells
- Myocytes, Cardiac*/metabolism
- Myocytes, Cardiac*/physiology
- Ribosomal Proteins*/genetics
- Ribosomal Proteins*/metabolism
- Zebrafish
- PubMed
- 41379537 Full text @ Elife
Citation
Nielsen, T., Kervadec, A., Theis, J.L., Missinato, M.A., Marchant, J., Romero, M., Marchetti, K., Lamba, A., Zeng, X.I., Berenguer, M., Walls, S.M., Schroeder, A., Birker, K., Duester, G., Grossfeld, P., Nelson, T.J., Olson, T.M., Ocorr, K., Bodmer, R., Vogler, G., Colas, A.R. (2025) Functional analysis across model systems implicates ribosomal proteins in growth and proliferation defects associated with hypoplastic left heart syndrome. eLIFE. 14:.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping