Abstract：
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a severe cardiac disease that leads to heart failure or sudden cardiac death (SCD). For the pathogenesis of ARVC, various mutations in at least eight different genes have been identified. A rare form of ARVC is associated with the mutation TMEM43 p.S358L, which is a fully penetrant variant in male carriers. TMEM43 p.S358 is homologous to CG8111 p.S333 in Drosophila melanogaster. We established CRISPR/Cas9-mediated CG8111 knock-out mutants in Drosophila, as well as transgenic fly lines carrying an overexpression construct of the CG8111 p.S333L substitution. Knock-out flies developed normally, whereas the overexpression of CG8111 p.S333L caused growth defects, loss of body weight, cardiac arrhythmias, and premature death. An evaluation of a series of model mutants that replaced S333 by selected amino acids proved that the conserved serine is critical for the physiological function of CG8111. Metabolomic and proteomic analyses revealed that the S333 in CG8111 is essential to proper energy homeostasis and lipid metabolism in the fly. Of note, metabolic impairments were also found in the murine Tmem43 disease model, and fibrofatty replacement is a hallmark of human ARVC5. These findings contribute to a more comprehensive understanding of the molecular functions of CG8111 in Drosophila, and can represent a valuable basis to assess the aetiology of the human TMEM43 p.S358L variant in more detail.
摘要：
致心律失常性右心室心肌病（ARVC）是一种严重的心脏病，可导致心力衰竭或心源性猝死（SCD）。对于ARVC的发病机制，已经鉴定出至少8种不同基因的各种突变。一种罕见形式的ARVC与突变TMEM43p.S358L有关，这是男性携带者的完全渗透变体。TMEM43p.S358与果蝇中的CG8111p.S333同源。我们在果蝇中建立了CRISPR/Cas9介导的CG8111敲除突变体，以及携带CG8111p.S333L取代的过表达构建体的转基因蝇系。敲除果蝇发育正常，而CG8111p.S333L的过表达导致生长缺陷，体重减轻,心律失常,过早死亡。用选定的氨基酸替换S333的一系列模型突变体的评估证明，保守的丝氨酸对于CG8111的生理功能至关重要。代谢组学和蛋白质组学分析显示，CG8111中的S333对于果蝇中适当的能量稳态和脂质代谢至关重要。值得注意的是，在鼠Tmem43疾病模型中也发现了代谢障碍，纤维脂肪替代是人ARVC5的标志。这些发现有助于更全面地了解CG8111在果蝇中的分子功能。并且可以代表更详细地评估人类TMEM43p.S358L变体的病因的有价值的基础。
