PUBLICATION
RRAGD variants cause cardiac dysfunction in a zebrafish model
- Authors
- Adella, A., Tengku, F., Arjona, F.J., Broekman, S., de Vrieze, E., van Wijk, E., Hoenderop, J.G.J., de Baaij, J.H.F.
- ID
- ZDB-PUB-240928-6
- Date
- 2024
- Source
- American journal of physiology. Heart and circulatory physiology 327(5): H1187-H1197 (Journal)
- Registered Authors
- Arjona, F.J., de Vrieze, Erik, van Wijk, Erwin
- Keywords
- RRAGD, cardiac dysfunction, mTORC1, rapamycin, zebrafish
- MeSH Terms
-
- Animals
- Disease Models, Animal
- Phenotype*
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- Heart Rate/drug effects
- Sirolimus*/pharmacology
- Stroke Volume/drug effects
- Zebrafish*
- MTOR Inhibitors/pharmacology
- Mutation
- Heart/drug effects
- Heart/embryology
- Heart/physiopathology
- PubMed
- 39331021 Full text @ Am. J. Physiol. Heart Circ. Physiol.
Citation
Adella, A., Tengku, F., Arjona, F.J., Broekman, S., de Vrieze, E., van Wijk, E., Hoenderop, J.G.J., de Baaij, J.H.F. (2024) RRAGD variants cause cardiac dysfunction in a zebrafish model. American journal of physiology. Heart and circulatory physiology. 327(5):H1187-H1197.
Abstract
The Ras-related GTP-binding protein D (RRAGD) gene plays a crucial role in cellular processes. Recently, RRAGD variants found in patients have been implicated in a novel disorder with kidney tubulopathy and dilated cardiomyopathy. Currently, the consequences of RRAGD variants at organismal level is unknown. Therefore, this study investigated the impact of RRAGD variants on cardiac function using zebrafish embryo model. Furthermore, the potential usage of rapamycin, an mTOR inhibitor, as a therapy was assessed in this model. Zebrafish embryos were injected with RRAGD p.S76L and p.P119R cRNA and the resulting heart phenotypes were studied. Our findings reveal that overexpression of RRAGD mutants resulted in decreased ventricular fractional shortening, ejection fraction, and pericardial swelling. In RRAGD S76L-injected embryos, lower survival and heartbeat were observed, while survival was unaffected in RRAGD P119R embryos. These observations were reversible following therapy with the mTOR inhibitor rapamycin. Moreover, no effects on electrolyte homeostasis were observed. Together, these findings indicate a crucial role of RRAGD for cardiac function. In the future, the molecular mechanisms by which RRAGD variants result in cardiac dysfunction, and if the effects of rapamycin are specific for RRAGD-dependent cardiomyopathy should be studied in clinical studies.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping