RRAGD variants cause cardiac dysfunction in a zebrafish model

Area of Science:

• Genetics
• Cardiology
• Developmental Biology

Background:

• Ras-related GTP-binding protein D (RRAGD) variants are linked to kidney tubulopathy and dilated cardiomyopathy.
• The organismal-level consequences of RRAGD variants remain largely unknown.
• Understanding RRAGD's role in cardiac function is crucial for disease mechanism elucidation.

Purpose of the Study:

• To investigate the impact of RRAGD variants on cardiac function using a zebrafish embryo model.
• To assess the therapeutic potential of rapamycin, an mTOR inhibitor, in RRAGD-associated cardiac dysfunction.
• To establish a model for studying rare cardiomyopathies linked to RRAGD.

Main Methods:

• Zebrafish embryos were injected with RRAGD p.S76L and p.P119R cRNA.
• Cardiac function was assessed by measuring ventricular fractional shortening and ejection fraction.
• Phenotypic changes, survival rates, and response to rapamycin treatment were analyzed.

Main Results:

• Overexpression of RRAGD mutants led to decreased cardiac function and pericardial swelling.
• RRAGD S76L mutants significantly reduced survival and heartbeat.
• Rapamycin treatment reversed the observed cardiac defects in zebrafish embryos.
• No significant effects on electrolyte homeostasis were detected.

Conclusions:

• RRAGD plays a critical role in maintaining normal cardiac function.
• Zebrafish embryos serve as a relevant model for RRAGD-dependent cardiomyopathy.
• Rapamycin shows therapeutic potential for RRAGD-associated cardiac dysfunction, warranting further clinical investigation.