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首页> 外文期刊>Human mutation >MT‐ATP6 MT‐ATP6 mitochondrial disease variants: Phenotypic and biochemical features analysis in 218 published cases and cohort of 14 new cases
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MT‐ATP6 MT‐ATP6 mitochondrial disease variants: Phenotypic and biochemical features analysis in 218 published cases and cohort of 14 new cases

机译：MT-ATP6 MT-ATP6线粒体疾病变体：表型和生化特征分析218例发表的14例新病例

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Abstract Mitochondrial complex V (CV) generates cellular energy as adenosine triphosphate (ATP). Mitochondrial disease caused by the m.8993TG pathogenic variant in the CV subunit gene MT‐ATP6 was among the first described human mitochondrial DNA diseases. Due to a lack of clinically available functional assays, validating the definitive pathogenicity of additional MT‐ATP6 variants remains challenging. We reviewed all reported MT‐ATP6 disease cases ( n ?=?218) to date, to assess for MT‐ATP6 variants, heteroplasmy levels, and inheritance correlation with clinical presentation and biochemical findings. We further describe the clinical and biochemical features of a new cohort of 14 kindreds with MT‐ATP6 variants of uncertain significance. Despite extensive overlap in the heteroplasmy levels of MT‐ATP6 variant carriers with and without a wide range of clinical symptoms, previously reported symptomatic subjects had significantly higher heteroplasmy load ( p ?=?2.2 x 10 ‐16 ). Pathogenic MT‐ATP6 variants resulted in diverse biochemical features. The most common findings were reduced ATP synthesis rate, preserved ATP hydrolysis capacity, and abnormally increased mitochondrial membrane potential. However, no single biochemical feature was universally observed. Extensive heterogeneity exists among both clinical and biochemical features of distinct MT‐ATP6 variants. Improved mechanistic understanding and development of consistent biochemical diagnostic analyses are needed to permit accurate pathogenicity assessment of variants of uncertain significance in MT‐ATP6.
机译：摘要线粒体复合体V（CV）为三磷酸腺苷（ATP）产生蜂窝能量。由M.8993T＆GT的线粒体疾病引起的CV亚基基因MT-ATP6中的致病变异是第一个描述的人体线粒体DNA疾病中。由于缺乏临床可用的功能测定，验证额外的MT-ATP6变体的最终致病性仍然具有挑战性。我们审查了所有报道的MT-ATP6病例（N？= 218），以评估MT-ATP6变体，异质水平和临床介绍和生物化学发现的遗传相关性。我们进一步描述了具有不确定意义的MT-ATP6变体的新群体的临床和生化特征。尽管在没有广泛的临床症状的MT-ATP6变体载体的异质水平中具有广泛的重叠，但先前报告的症状受试者具有显着高的异质载荷（P？=？2.2 x 10 -16）。病原MT-ATP6变体导致生化特征不同。最常见的发现减少了ATP合成率，保存的ATP水解能力，并且异常增加的线粒体膜电位。但是，没有普遍观察到单一的生化特征。在不同的MT-ATP6变体的临床和生化特征中存在广泛的异质性。需要改善一致生化诊断分析的机械理解和发展，以允许准确的致病性评估MT-ATP6中不确定意义的变异性。

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