Rescue of primary ubiquinone deficiency due to a novel COQ7 defect using 2,4-dihydroxybensoic acid
Rescue of primary ubiquinone deficiency due to a novel COQ7 defect using 2,4-dihydroxybensoic acid
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DOI：
10.1136/jmedgenet-2015-102986
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发表时间：
2015-11-01
影响因子：
4
通讯作者：
Wedell, Anna
中科院分区：
文献类型：
--
作者：
Freyer, Christoph;Stranneheim, Henrik;Wedell, Anna
背景 辅酶 Q 是大多数细胞膜中重要的线粒体电子载体、氧化还原辅因子和有效的抗氧化剂。辅酶 Q 缺乏与一系列代谢疾病以及一些药物治疗和衰老有关。方法我们使用全外显子组测序 (WES) 来调查患有遗传性代谢疾病的患者，并应用新型超高压液相色谱质谱法来测量患者样本中的辅酶 Q。结果我们在患有复杂线粒体缺陷的患者中发现了 COQ7 基因的纯合错义突变，导致辅酶 Q 水平严重降低我们证明辅酶 Q 类似物2,4-二羟基苯索酸 (2,4DHB) 能够特异性绕过 COQ7 缺陷，提高细胞辅酶 Q 水平并挽救患者成纤维细胞的生化缺陷。 结论 我们报道了第一例因纯合 COQ7 突变而导致原发性辅酶 Q 缺陷的患者，并使用 2,4DHB 进行潜在有益的治疗。
Background Coenzyme Q is an essential mitochondrial electron carrier, redox cofactor and a potent antioxidant in the majority of cellular membranes. Coenzyme Q deficiency has been associated with a range of metabolic diseases, as well as with some drug treatments and ageing.Methods We used whole exome sequencing (WES) to investigate patients with inherited metabolic diseases and applied a novel ultra-pressure liquid chromatographymass spectrometry approach to measure coenzyme Q in patient samples.Results We identified a homozygous missense mutation in the COQ7 gene in a patient with complex mitochondrial deficiency, resulting in severely reduced coenzyme Q levels We demonstrate that the coenzyme Q analogue 2,4-dihydroxybensoic acid (2,4DHB) was able to specifically bypass the COQ7 deficiency, increase cellular coenzyme Q levels and rescue the biochemical defect in patient fibroblasts.Conclusion We report the first patient with primary coenzyme Q deficiency due to a homozygous COQ7 mutation and a potentially beneficial treatment using 2,4DHB.