初级辅酶Q10(CoQ10)缺乏症是一组由CoQ10生物合成缺陷引起的先天性代谢错误。COQ7中的双等位基因致病变体,编码线粒体5-脱甲氧基泛醌羟化酶,已经报告了来自七个家庭的九名患者。我们确定了5名新的患者与COQ7相关的原发性CoQ10缺乏症,对患者进行临床评估,并研究了目前和以前报道的COQ7变异体的功能效应和潜在的治疗方案.主要临床特征包括新生儿发病表现为严重的神经肌肉,心肺和肾脏受累和迟发性疾病表现为进行性神经病,下肢无力,步态异常,和可变的发育延迟。在氧化碳源上生长需要COQ7的Baker酵母直向同源物CAT5,而cat5Δ菌株显示出氧化生长缺陷。野生型CAT5的表达可以完全挽救缺陷;然而,酵母CAT5具有等效的人类致病变体。有趣的是,cat5Δ酵母含有p.Arg57Gln(相当于人p.Arg54Gln),p.Arg112Trp(相当于p.Arg107Trp),p.Ile69Asn(相当于p.Ile66Asn)和p.Lys108Met和p.Leu116Pro(相当于复杂等位基因p.[Thr103Met;Leu111Pro])的组合部分挽救了生长缺陷,表明这些变体是低态等位基因。补充2,4-二羟基苯甲酸(2,4-diHB)挽救了泄漏和严重突变体的生长缺陷。COQ8和2,4-diHB补充剂的过表达协同地恢复了氧化生长和呼吸缺陷。总的来说,我们定义了COQ7相关疾病的两种不同的疾病表现,这些疾病表现具有新出现的基因型-表型相关性,并验证了酵母模型在COQ7变异体功能研究中的应用.
Primary coenzyme Q10 (CoQ10) deficiency is a group of inborn errors of metabolism caused by defects in CoQ10 biosynthesis. Biallelic pathogenic variants in COQ7, encoding mitochondrial 5-demethoxyubiquinone hydroxylase, have been reported in nine patients from seven families. We identified five new patients with COQ7-related primary CoQ10 deficiency, performed clinical assessment of the patients, and studied the functional effects of current and previously reported COQ7 variants and potential treatment options. The main clinical features included a neonatal-onset presentation with severe neuromuscular, cardiorespiratory and renal involvement and a late-onset disease presenting with progressive neuropathy, lower extremity weakness, abnormal gait, and variable developmental delay. Baker\'s yeast orthologue of COQ7, CAT5, is required for growth on oxidative carbon sources and cat5Δ strain demonstrates oxidative growth defect. Expression of wild-type CAT5 could completely rescue the defect; however, yeast CAT5 harboring equivalent human pathogenic variants could not. Interestingly, cat5Δ yeast harboring p.Arg57Gln (equivalent to human p.Arg54Gln), p.Arg112Trp (equivalent to p.Arg107Trp), p.Ile69Asn (equivalent to p.Ile66Asn) and combination of p.Lys108Met and p.Leu116Pro (equivalent to the complex allele p.[Thr103Met;Leu111Pro]) partially rescued the growth defects, indicating these variants are hypomorphic alleles. Supplementation with 2,4 dihydroxybenzoic acid (2,4-diHB) rescued the growth defect of both the leaky and severe mutants. Overexpression of COQ8 and 2,4-diHB supplementation synergistically restored oxidative growth and respiratory defect. Overall, we define two distinct disease presentations of COQ7-related disorder with emerging genotype-phenotype correlation and validate the use of the yeast model for functional studies of COQ7 variants.