A severe form of infantile cardiomyopathy (CM) has been linked to ELAC2 gene mutations. ELAC2 is a highly conserved human gene. It encodes RNaseZL endoribonuclease that plays an essential role in the production of mature tRNAs. To establish a causal connection between ELAC2 variants and CM, here we use a model organism Drosophila melanogaster, which carries ELAC2 homolog - dRNaseZ. Even though dRNaseZ and ELAC2 have diverged in some of their biological functions, our study demonstrates the utility of the fly model to study the mechanism of ELAC2 related pathology. We established transgenic lines harboring dRNaseZ with CM-linked mutations in the background of endogenous dRNaseZ knockout. Importantly, we found that the phenotype of these flies is consistent with pathological features in human patients. Specifically, expression of CM-linked variants in flies causes heart hypertrophy and leads 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 lay the foundation to improve our understanding and diagnosis of this rare infantile disease.

During the revision process, and at the request of reviewers, alternative software was used to represent the data shown in Fig. 5D. Unfortunately, incorrect data were used during the replotting. Fig. 5D has now been plotted with the correct primary data described in the paper. The results and conclusions remain unaffected.