Abstract：
The protein encoded by COQ7 is required for CoQ10 synthesis in humans, hydroxylating 3-demethoxyubiquinol (DMQ10) in the second to last steps of the pathway. COQ7 mutations lead to a primary CoQ10 deficiency syndrome associated with a pleiotropic neurological disorder. This study shows the clinical, physiological, and molecular characterization of four new cases of CoQ10 primary deficiency caused by five mutations in COQ7, three of which have not yet been described, inducing mitochondrial dysfunction in all patients. However, the specific combination of the identified variants in each patient generated precise pathophysiological and molecular alterations in fibroblasts, which would explain the differential in vitro response to supplementation therapy. Our results suggest that COQ7 dysfunction could be caused by specific structural changes that affect the interaction with COQ9 required for the DMQ10 presentation to COQ7, the substrate access to the active site, and the maintenance of the active site structure. Remarkably, patients\' fibroblasts share transcriptional remodeling, supporting a modification of energy metabolism towards glycolysis, which could be an adaptive mechanism against CoQ10 deficiency. However, transcriptional analysis of mitochondria-associated pathways showed distinct and dramatic differences between patient fibroblasts, which correlated with the extent of pathophysiological and neurological alterations observed in the probands. Overall, this study suggests that the combination of precise genetic diagnostics and the availability of new structural models of human proteins could help explain the origin of phenotypic pleiotropy observed in some genetic diseases and the different responses to available therapies.
摘要：
由COQ7编码的蛋白质是人类合成CoQ10所必需的，在途径的第二个到最后一个步骤中羟基化3-去甲氧基泛醇（DMQ10）。COQ7突变导致与多效性神经系统疾病相关的原发性CoQ10缺乏综合征。这项研究表明，临床，生理,以及由COQ7中的五个突变引起的四个新的CoQ10原发性缺乏病例的分子特征，其中三个尚未被描述，在所有患者中诱导线粒体功能障碍。然而,每个患者中鉴定的变体的特定组合在成纤维细胞中产生了精确的病理生理和分子改变，这可以解释体外对补充治疗的不同反应。我们的结果表明，COQ7功能障碍可能是由特定的结构变化引起的，这些结构变化会影响DMQ10呈递至COQ7所需的与COQ9的相互作用，即底物进入活性位点。以及活动站点结构的维护。值得注意的是,患者成纤维细胞共享转录重塑，支持能量代谢向糖酵解的改变，这可能是一种针对辅酶Q10缺乏的适应性机制。然而,线粒体相关途径的转录分析显示，患者成纤维细胞之间存在明显差异，这与先证者中观察到的病理生理和神经系统改变的程度相关。总的来说,这项研究表明，精确的遗传诊断和新的人类蛋白质结构模型的结合可以帮助解释在某些遗传疾病中观察到的表型多效性的起源以及对可用疗法的不同反应。
