Department of Biological Sciences, Fordham University, Bronx, NY, United States of America.
Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, United States of America.
PLoS One. 2023 May 25;18(5):e0286214. doi: 10.1371/journal.pone.0286214. eCollection 2023.
Cardiomyopathy (CM) is a group of diseases distinguished by morphological and functional abnormalities in the myocardium. It is etiologically heterogeneous and may develop via cell autonomous and/or non-autonomous mechanisms. One of the most severe forms of CM has been linked to the deficiency of the ubiquitously expressed RNase Z endoribonuclease. RNase Z cleaves off the 3'-trailer of both nuclear and mitochondrial primary tRNA (pre-tRNA) transcripts. Cells mutant for RNase Z accumulate unprocessed pre-tRNA molecules. Patients carrying RNase Z variants with reduced enzymatic activity display a plethora of symptoms including muscular hypotonia, microcephaly and severe heart hypertrophy; still, they die primarily due to acute heart decompensation. Determining whether the underlying mechanism of heart malfunction is cell autonomous or not will provide an opportunity to develop novel strategies of more efficient treatments for these patients. In this study, we used CRISPR-TRiM technology to create Drosophila models that carry cardiomyopathy-linked alleles of RNase Z only in the cardiomyocytes. We found that this modification is sufficient for flies to develop heart hypertrophy and systolic dysfunction. These observations support the idea that the RNase Z linked CM is driven by cell autonomous mechanisms.
心肌病（CM）是一组以心肌形态和功能异常为特征的疾病。其病因具有异质性，可能通过细胞自主和/或非自主机制发展。CM 最严重的形式之一与普遍表达的 RNase Z 内切核糖核酸酶的缺乏有关。RNase Z 切割核和线粒体初级 tRNA（pre-tRNA）转录本的 3'-尾部。RNase Z 突变的细胞积累未加工的 pre-tRNA 分子。携带 RNase Z 变体、酶活性降低的患者表现出多种症状，包括肌肉张力减退、小头症和严重的心脏肥大；尽管如此，他们主要死于急性心脏失代偿。确定心脏功能障碍的潜在机制是否为细胞自主，将为这些患者提供开发更有效治疗新策略的机会。在这项研究中，我们使用 CRISPR-TRiM 技术在心肌细胞中仅创建携带与心肌病相关的 RNase Z 等位基因的果蝇模型。我们发现这种修饰足以使果蝇发展出心脏肥大和收缩功能障碍。这些观察结果支持了 RNase Z 相关 CM 是由细胞自主机制驱动的观点。
