TY - JOUR
T1 - ELAC2/RNaseZ-linked cardiac hypertrophy in Drosophila melanogaster
AU - Migunova, Ekaterina
AU - Theophilopoulos, Joanna
AU - Mercadante, Marisa
AU - Men, Jing
AU - Zhou, Chao
AU - Dubrovsky, Edward B.
N1 - Publisher Copyright:
© 2021. Published by The Company of Biologists Ltd.
PY - 2021/8
Y1 - 2021/8
N2 - 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.
AB - 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.
KW - Cardiomyopathy
KW - Drosophila
KW - ELAC2
KW - OCM
KW - RNase Z
UR - http://www.scopus.com/inward/record.url?scp=85114733295&partnerID=8YFLogxK
U2 - 10.1242/DMM.048931
DO - 10.1242/DMM.048931
M3 - Article
C2 - 34338278
AN - SCOPUS:85114733295
SN - 1754-8403
VL - 14
JO - DMM Disease Models and Mechanisms
JF - DMM Disease Models and Mechanisms
IS - 8
M1 - dmm048931
ER -