PDF(Pubmed)
Abstract：
SELENON-Related Myopathy (SELENON-RM) is a rare congenital myopathy caused by mutations of the SELENON gene characterized by axial muscle weakness and progressive respiratory insufficiency. Muscle histopathology commonly includes multiminicores or a dystrophic pattern but is often non-specific. The SELENON gene encodes selenoprotein N (SelN), a selenocysteine-containing redox enzyme located in the endo/sarcoplasmic reticulum membrane where it colocalizes with mitochondria-associated membranes. However, the molecular mechanism(s) by which SelN deficiency causes SELENON-RM are undetermined. A hurdle is the lack of cellular and animal models that show assayable phenotypes. Here we report deep-phenotyping of SelN-deficient zebrafish and muscle cells. SelN-deficient zebrafish exhibit changes in embryonic muscle function and swimming activity in larvae. Analysis of single cell RNAseq data in a zebrafish embryo-atlas revealed coexpression between selenon and genes involved in glutathione redox pathway. SelN-deficient zebrafish and mouse myoblasts exhibit changes in glutathione and redox homeostasis, suggesting a direct relationship with SelN function. We report changes in metabolic function abnormalities in SelN-null myotubes when compared to WT. These results suggest that SelN has functional roles during zebrafish early development and myoblast metabolism.
摘要：
SELENON相关肌病（SELENON-RM）是一种罕见的先天性肌病，由SELENON基因突变引起，以轴系肌无力和进行性呼吸功能不全为特征。肌肉组织病理学通常包括多微细胞或营养不良模式，但通常是非特异性的。SELENON基因编码硒蛋白N（SelN），一种含硒代半胱氨酸的氧化还原酶，位于内/肌浆网膜，与线粒体相关膜共定位。然而,SelN缺乏导致SELENON-RM的分子机制尚未确定。一个障碍是缺乏显示可测定表型的细胞和动物模型。在这里，我们报告了SelN缺陷斑马鱼和肌肉细胞的深层表型。缺乏SelN的斑马鱼在幼虫中表现出胚胎肌肉功能和游泳活动的变化。斑马鱼胚胎图谱中单细胞RNAseq数据的分析揭示了硒和参与谷胱甘肽氧化还原途径的基因之间的共表达。缺乏SelN的斑马鱼和小鼠成肌细胞表现出谷胱甘肽和氧化还原稳态的变化，表明与SelN功能有直接关系。我们报告了与WT相比，SelN无效肌管代谢功能异常的变化。这些结果表明，SelN在斑马鱼早期发育和成肌细胞代谢中具有功能作用。
