<i>RRAGD</i> variants cause cardiac dysfunction in a zebrafish model

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