variants cause cardiac dysfunction in a zebrafish model.

Abstract

The Ras-related GTP-binding protein D () gene plays a crucial role in cellular processes. Recently,variants found in patients have been implicated in a novel disorder with kidney tubulopathy and dilated cardiomyopathy. Currently, the consequences ofvariants at the organismal level are unknown. Therefore, this study investigated the impact ofvariants 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 withp.S76L and p.P119R cRNA and the resulting heart phenotypes were studied. Our findings reveal that overexpression ofmutants resulted in decreased ventricular fractional shortening, ejection fraction, and pericardial swelling. InS76L-injected embryos, lower survival and heartbeat were observed, whereas survival was unaffected inP119R 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 ofin cardiac function. In the future, the molecular mechanisms by whichvariants result in cardiac dysfunction and if the effects of rapamycin are specific for-dependent cardiomyopathy should be studied in clinical studies.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.