ELAC2/RNaseZ-linked cardiac hypertrophy in Drosophila melanogaster.
ELAC2/RNaseZ-linked cardiac hypertrophy in Drosophila melanogaster.
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DOI：
10.1242/dmm.048931
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发表时间：
2021-08-01
影响因子：
4.3
通讯作者：
Dubrovsky EB
中科院分区：
文献类型：
--
作者：
Migunova E;Theophilopoulos J;Mercadante M;Men J;Zhou C;Dubrovsky EB
一种严重形式的婴儿心肌病（CM）与高度保守的人类基因ELAC2突变有关。它编码锌磷酸二酯酶ELAC蛋白2 (ELAC2)，在成熟trna的产生中起着至关重要的作用。为了建立ELAC2变异与CM之间的因果关系，我们使用了携带ELAC2同源RNaseZ的黑腹果蝇模型生物。尽管RNaseZ和ELAC2在某些生物学功能上存在分歧，但我们的研究证明了使用果蝇模型来研究ELAC2相关病理的机制。在内源性RNaseZ基因敲除的背景下，我们建立了含有cm连锁突变RNaseZ的转基因系。重要的是，我们发现这些果蝇的表型与人类患者的病理特征一致。具体来说，在果蝇中，CM相关变异的表达导致心脏肥大，并导致与一种罕见的CM相关的心脏收缩力降低。本研究为探究引起cm的ELAC2蛋白突变的致病性提供了第一个实验证据，为提高我们对这一罕见婴儿疾病的认识和诊断奠定了基础。摘要：一个新建立的果蝇模型概括了与ELAC2突变相关的人类心脏病理的关键特征，从而为ELAC2变异的致病性提供了实验证据。
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. . Summary: A newly established Drosophila model recapitulates key features of human heart pathology linked to mutations in ELAC2, thus providing experimental evidence of the pathogenicity of ELAC2 variants.
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影响因子：
37.8
作者：
Harris, Kevin M.;Spirito, Paolo;Maron, Barry J.
通讯作者：
Maron, Barry J.
影响因子：
4
作者：
Farrell ET;Grimes AC;de Lange WJ;Armstrong AE;Ralphe JC
通讯作者：
Ralphe JC
影响因子：
9.8
作者：
Haack, Tobias B.;Kopajtich, Robert;Prokisch, Holger
通讯作者：
Prokisch, Holger
影响因子：
2.3
作者：
Dellefave L;McNally EM
通讯作者：
McNally EM
影响因子：
1.9
作者：
Guzzo-Merello, Gonzalo;Cobo-Marcos, Marta;Garcia-Pavia, Pablo
通讯作者：
Garcia-Pavia, Pablo