De novo mutations in the mitochondrial ND3 gene as a cause of infantile mitochondrial encephalopathy and complex I deficiency
De novo mutations in the mitochondrial ND3 gene as a cause of infantile mitochondrial encephalopathy and complex I deficiency
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DOI：
10.1002/ana.10787
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发表时间：
2004-01-01
影响因子：
11.2
通讯作者：
Thorburn, DR
中科院分区：
文献类型：
--
作者：
McFarland, R;Kirby, DM;Thorburn, DR
核和线粒体DNA突变都可能导致能量产生障碍。呼吸链复合物I缺乏症是最常见的能量生成障碍，也是婴儿线粒体脑病如利氏病和致死性婴儿线粒体病的常见原因。大多数这样的情况下，已被假定为核基因缺陷引起的，但最近已被证明是由突变引起的，在神经系统编码的复合物I亚基基因ND4，ND5和ND6。我们报告的前四例婴儿线粒体脑病引起的ND3亚基基因突变。三个无关的孩子有相同的新异质突变（T10158C），只有第二个突变报告在ND3，和一个有以前确定的T10191C突变。这两种突变导致酶活性的降低不成比例地大于完全组装的复合物I的量，这表明ND3亚基在电子传递、质子泵或泛醌结合中起着未知但重要的作用。三个病例似乎有一个新生突变，在母系亲属中没有检测到突变。线粒体DNA疾病在儿科人群中的流行率可能比目前预测的要高得多，并且应该考虑患有婴儿线粒体脑病和复合体I缺乏症的患者。
Both nuclear and mitochondrial DNA mutations can cause energy generation disorders. Respiratory chain complex I deficiency is the most common energy generation disorder and a frequent cause of infantile mitochondrial encephalopathies such as Leigh's disease and lethal infantile mitochondrial disease. Most such cases have been assumed to be caused by nuclear gene defects, but recently an increasing number have been shown to be caused by mutations in the mitochondrially encoded complex I subunit genes ND4, ND5, and ND6. We report the first four cases of infantile mitochondrial encephalopathies caused by mutations in the ND3 subunit gene. Three unrelated children have the same novel heteroplasmic mutation (T10158C), only the second mutation reported in ND3, and one has the previously identified T10191C mutation. Both mutations cause disproportionately greater reductions in enzyme activity than in the amount of fully assembled complex I, suggesting the ND3 subunit plays an unknown but important role in electron transport, proton pumping, or ubiquinone binding. Three cases appear to have a de novo mutation, with no mutation detected in maternal relatives. Mitochondrial DNA disease may be considerably more prevalent in the pediatric population than currently predicted and should be considered in patients with infantile mitochondrial encephalopathies and complex I deficiency.