| Autor: |
Adella A; Department of Medical BioSciences, Radboud University Medical Center, Nijmegen, The Netherlands., Tengku F; Department of Medical BioSciences, Radboud University Medical Center, Nijmegen, The Netherlands., Arjona FJ; Department of Medical BioSciences, Radboud University Medical Center, Nijmegen, The Netherlands., Broekman S; Department of Otorhinolaryngology, Radboud University Medical Center, Nijmegen, The Netherlands., de Vrieze E; Department of Otorhinolaryngology, Radboud University Medical Center, Nijmegen, The Netherlands., van Wijk E; Department of Otorhinolaryngology, Radboud University Medical Center, Nijmegen, The Netherlands., Hoenderop JGJ; Department of Medical BioSciences, Radboud University Medical Center, Nijmegen, The Netherlands., de Baaij JHF; Department of Medical BioSciences, Radboud University Medical Center, Nijmegen, The Netherlands. |
| Abstrakt: |
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 the organismal level are unknown. Therefore, this study investigated the impact of RRAGD variants on cardiac function using a 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, whereas 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 in 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. NEW & NOTEWORTHY The resultant heart-associated phenotypes in the zebrafish embryos of this study serve as a valuable experimental model for this rare cardiomyopathy. Moreover, the potential therapeutic property of rapamycin in cardiac dysfunctions was highlighted, making this study a pivotal step toward prospective clinical applications. |
