TANGO2 variants result in a complex disease phenotype consisting of recurrent crisis‐induced rhabdomyolysis, encephalopathy, seizures, lactic acidosis, hypoglycemia, and cardiac arrhythmias. Although first described in a fruit fly model as a protein necessary for some aspect of Golgi function and organization, its role in the cell at a fundamental level has not been addressed. Such studies are necessary to better counsel families regarding treatment options and nutrition management to mitigate the metabolic aspects of the disease. The few studies performed to address the pathway(s) in which TANGO2 functions have led to enigmatic results, with some suggesting defects in membrane traffic while others suggest unknown mitochondrial defects. Here, we have performed a robust membrane trafficking assay on fibroblasts derived from three different individuals harboring TANGO2 variants and show that there is a significant delay in the movement of cargo between the endoplasmic reticulum and the Golgi. Importantly, this delay was attributed to a defect in TANGO2 function. We further show that a portion of TANGO2 protein localizes to the mitochondria through a necessary but not sufficient stretch of amino acids at the amino terminus of the protein. Fibroblasts from affected individuals also displayed changes in mitochondrial morphology. We conclude that TANGO2 functions in both membrane trafficking and in some as yet undetermined role in mitochondria physiology. The phenotype of affected individuals can be partially explained by this dual involvement of the protein.

中文翻译：

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与 TANGO2 变异相关的表型可以通过蛋白质在 ER 到高尔基体转运和线粒体中的双重作用来解释

TANGO2 变异导致复杂的疾病表型，包括反复危象诱发的横纹肌溶解、脑病、癫痫、乳酸性酸中毒、低血糖和心律失常。尽管首先在果蝇模型中被描述为高尔基体功能和组织的某些方面所必需的蛋白质，但它在细胞中的基本作用尚未得到解决。此类研究对于更好地为家庭提供治疗选择和营养管理方面的咨询以减轻疾病的代谢方面是必要的。为解决 TANGO2 功能导致神秘结果的途径而进行的少数研究，有些表明膜运输存在缺陷，而另一些则表明存在未知的线粒体缺陷。这里，我们对来自携带 TANGO2 变体的三个不同个体的成纤维细胞进行了强大的膜运输分析，结果表明内质网和高尔基体之间的货物运动存在显着延迟。重要的是，这种延迟归因于 TANGO2 功能的缺陷。我们进一步表明，部分 TANGO2 蛋白通过蛋白质氨基末端的一段必要但不充分的氨基酸序列定位于线粒体。来自受影响个体的成纤维细胞也显示出线粒体形态的变化。我们得出结论，TANGO2 在膜运输和线粒体生理学中的某些尚未确定的作用中起作用。受影响个体的表型可以通过蛋白质的这种双重参与来部分解释。