Ohnuma Kohei, Kishita Yoshihito, Nyuzuki Hiromi, Kohda Masakazu, Ohtsu Yuta, Takeo Satomi, Asano Tsunaki, Sato-Miyata Yukiko, Ohtake Akira, Murayama Kei, Okazaki Yasushi, Aigaki Toshiro
Department of Biological Sciences, Graduate School of Science and Engineering, Tokyo Metropolitan University, Hachioji-shi, Japan.
Intractable Disease Research Center, Graduate School of Medicine, Juntendo University, Bunkyo-ku, Japan.
FEBS Lett. 2020 Apr 15. doi: 10.1002/1873-3468.13792.
Tetratricopeptide repeat protein 37 (TTC37) is a causative gene of trichohepatoenteric syndrome (THES). However, little is known about the pathogenesis of this disease. Here, we characterize the phenotype of a Drosophila model in which ski3, a homolog of TTC37, is disrupted. The mutant flies are pupal lethal, and the pupal lethality is partially rescued by transgenic expression of wild-type ski3 or human TTC37. The mutant larvae show growth retardation, heart arrhythmia, triacylglycerol accumulation, and aberrant metabolism of glycolysis and the TCA cycle. Moreover, mitochondrial membrane potential and respiratory chain complex activities are significantly reduced in the mutants. Our results demonstrate that ski3 deficiency causes mitochondrial dysfunction, which may underlie the pathogenesis of THES.
四肽重复蛋白37（TTC37）是毛发肝肠综合征（THES）的致病基因。然而，关于这种疾病的发病机制知之甚少。在此，我们对果蝇模型的表型进行了表征，其中TTC37的同源物ski3被破坏。突变果蝇在蛹期致死，野生型ski3或人类TTC37的转基因表达可部分挽救蛹期致死。突变幼虫表现出生长迟缓、心律失常、三酰甘油积累以及糖酵解和三羧酸循环的异常代谢。此外，突变体中线粒体膜电位和呼吸链复合体活性显著降低。我们的结果表明，ski3缺陷导致线粒体功能障碍，这可能是THES发病机制的基础。
