Abstract：
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a rare autosomal recessive metabolic disease. Patients present with metabolic decompensation, muscle weakness, respiratory failure, and cardiomyopathy. Late-onset MADD is primarily caused by mutations in the ETFDH gene. Here, we report a patient who has been diagnosed with Down syndrome after birth following karyotype analysis and simultaneously carrying compound heterozygous variants of ETFDH (c.3G > C (p. M1?); c.725C > T (p. T242I), which is novel). Further molecular analyses revealed that the novel c.725C > T (p. T242I) mutation enhances the degradation of electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO) via the ubiquitin proteasome pathway. Five ubiquitin E3 ligases (STUB1, RNF40, UBE3C, CUL3, and CUL1) and one ubiquitin modification site (Cystein, C101) of the ETF-QO were reported in this study. Our study not only expanded the pathogenic variant spectrum of ETFDH gene but also proved that the c.725C > T (p. T242I) will promote protein degradation through ubiquitin proteasome pathway.
摘要：
多发性酰基辅酶A脱氢酶缺乏症（MADD）是一种罕见的常染色体隐性代谢疾病。存在代谢失代偿的患者，肌肉无力,呼吸衰竭,和心肌病。迟发性MADD主要由ETFDH基因突变引起。这里,我们报告了一名患者，该患者在核型分析后出生后被诊断为唐氏综合征，并同时携带ETFDH的复合杂合变体（c.3G>C（p。M1？）；c.725C>T（p。T242I),这是新颖的）。进一步的分子分析表明，新的c.725C>T（p。T242I）突变通过泛素蛋白酶体途径增强电子转移黄素蛋白-泛醌氧化还原酶（ETF-QO）的降解。五种泛素E3连接酶(STUB1，RNF40，UBE3C，CUL3和CUL1）和一个泛素修饰位点（Cystein，本研究报告了ETF-QO的C101)。我们的研究不仅扩展了ETFDH基因的致病变异谱，而且证明了c.725C>T（p。T242I）将通过泛素蛋白酶体途径促进蛋白质降解。
