Abstract
A severe form of infantile cardiomyopathy (CM) has been linked to mutations in ELAC2, a highly conserved human gene. It encodes Zinc phosphodiesterase ELAC protein 2 (ELAC2), which plays an essential role in the production of mature tRNAs. To establish a causal connection between ELAC2 variants and CM, here we used the Drosophila melanogaster model organism, which carries the ELAC2 homolog RNaseZ. Even though RNaseZ and ELAC2 have diverged in some of their biological functions, our study demonstrates the use of the fly model to study the mechanism of ELAC2-related pathology. We established transgenic lines harboring RNaseZ with CM-linked mutations in the background of endogenous RNaseZ knockout. Importantly, we found that the phenotype of these flies is consistent with the pathological features in human patients. Specifically, expression of CM-linked variants in flies caused heart hypertrophy and led to reduction in cardiac contractility associated with a rare form of CM. This study provides first experimental evidence for the pathogenicity of CM-causing mutations in the ELAC2 protein, and the foundation to improve our understanding and diagnosis of this rare infantile disease. This article has an associated First Person interview with the first author of the paper.