Experimental models.

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（Cardiomyopathy, CM）是一组以心肌（myocardium）形态与功能异常为特征的疾病。该病病因学异质性显著，可通过细胞自主性及/或非细胞自主性机制发病。其中一类最严重的心肌病与普遍表达的RNase Z核糖核酸内切酶（RNase Z）缺乏相关。RNase Z可切割细胞核与线粒体来源的初级转运RNA（primary tRNA, pre-tRNA）转录本的3’端尾随序列。RNase Z突变细胞会积累未加工的pre-tRNA分子。携带酶活性降低的RNase Z变异体的患者会出现多种临床症状，包括肌张力减退、小头畸形及重度心脏肥大，但此类患者最终仍主要死于急性心功能失代偿。明确心脏功能异常的核心机制是否为细胞自主性，将为开发针对此类患者的更高效治疗策略提供重要契机。本研究采用CRISPR-TRiM技术构建了仅在心肌细胞（cardiomyocytes）中携带心肌病相关RNase Z等位基因的果蝇（Drosophila）模型。研究发现，该基因修饰足以使果蝇出现心脏肥大与收缩功能障碍。上述实验结果支持"RNase Z相关心肌病由细胞自主性机制驱动"这一学术观点。