MT-ATP6 mitochondrial disease variants: Phenotypic and biochemical features analysis in 218 published cases and cohort of 14 new cases
MT-ATP6 mitochondrial disease variants: Phenotypic and biochemical features analysis in 218 published cases and cohort of 14 new cases
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DOI：
10.1002/humu.23723
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发表时间：
2019-05-01
期刊：
影响因子：
3.9
通讯作者：
Falk, Marni J.
中科院分区：
文献类型：
--
作者：
Ganetzky, Rebecca D.;Stendel, Claudia;Falk, Marni J.
线粒体复合物V（CV）以三磷酸腺苷（ATP）的形式产生细胞能量。由CV亚基基因MT-ATP 6中的m.8993T>G致病变体引起的线粒体疾病是最早描述的人类线粒体DNA疾病之一。由于缺乏临床可用的功能测定，验证其他MT-ATP 6变体的确定致病性仍然具有挑战性。我们回顾了迄今为止所有确诊的MT-ATP 6疾病病例（n = 218），以评估MT-ATP 6变异、异质性水平以及与临床表现和生化结果的遗传相关性。我们进一步描述了一个新的队列的临床和生化特征的14个激酶MT-ATP 6变异的不确定的意义。尽管MT-ATP 6变异携带者的异质性水平有广泛的重叠，有和没有广泛的临床症状，以前报道的症状受试者有显着较高的异质性负荷（p = 2.2 × 10（-16））。致病性MT-ATP 6变体导致不同的生化特征。最常见的发现是ATP合成速率降低，ATP水解能力保留，线粒体膜电位异常升高。然而，没有一个单一的生化特征是普遍观察。不同MT-ATP 6变体的临床和生化特征之间存在广泛的异质性。需要改进的机制理解和一致的生化诊断分析的发展，以允许MT-ATP 6中不确定意义的变体的准确致病性评估。
Mitochondrial complex V (CV) generates cellular energy as adenosine triphosphate (ATP). Mitochondrial disease caused by the m.8993T>G 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 reportedMT-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.