Abstract

Electron transfer flavoprotein dehydrogenase, also called ETF-ubiquinone oxidoreductase (ETF-QO), is a protein localized in the inner membrane of mitochondria, playing a central role in the electron-transfer system. Indeed, ETF-QO mediates electron transport from flavoprotein dehydrogenases to the ubiquinone pool. ETF-QO mutations are often associated with riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency (RR-MADD, OMIM#231680), a multisystem genetic disease characterized by various clinical manifestations with different degrees of severity. In this review, we outline the clinical features correlated with ETF-QO deficiency and the benefits obtained from different treatments, such as riboflavin, L-carnitine and/or coenzyme Q10 supplementation, and a diet poor in fat and protein. Moreover, we provide a detailed summary of molecular and bioinformatic investigations, describing the mutations identified in ETFDH gene and highlighting their predicted impact on enzymatic structure and activity. In addition, we report biochemical and functional analysis, performed in HEK293 cells and patient fibroblasts and muscle cells, to show the relationship between the nature of ETFDH mutations, the variable impairment of enzyme function, and the different degrees of RR-MADD severity. Finally, we describe in detail 5 RR-MADD patients carrying different ETFDH mutations and presenting variable degrees of clinical symptom severity.

摘要

电子转移黄素蛋白脱氢酶，也称为 ETF-泛醌氧化还原酶 (ETF-QO)，是一种定位于线粒体内膜的蛋白质，在电子转移系统中起核心作用。事实上，ETF-QO 介导电子从黄素蛋白脱氢酶传递到泛醌池。ETF-QO 突变通常与核黄素反应性多酰基辅酶 A 脱氢酶缺乏症 (RR-MADD, OMIM#231680) 相关，这是一种多系统遗传疾病，其特征在于具有不同严重程度的各种临床表现。在这篇综述中，我们概述了与 ETF-QO 缺乏相关的临床特征以及从不同治疗中获得的益处，如核黄素、左旋肉碱和/或辅酶 Q10 补充剂，以及脂肪和蛋白质含量低的饮食。而且，ETFDH基因并强调它们对酶结构和活性的预测影响。此外，我们报告了在 HEK293 细胞和患者成纤维细胞和肌肉细胞中进行的生化和功能分析，以显示ETFDH突变的性质、酶功能的可变损伤以及不同程度的 RR-MADD 严重程度之间的关系。最后，我们详细描述了 5 名携带不同ETFDH突变并呈现不同程度临床症状严重性的RR-MADD 患者。