A novel mitochondrial m.14430A>G (MT-ND6, p.W82R) variant causes complex I deficiency and mitochondrial Leigh syndrome
A novel mitochondrial m.14430A>G (MT-ND6, p.W82R) variant causes complex I deficiency and mitochondrial Leigh syndrome
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DOI：
10.1515/cclm-2020-0150
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发表时间：
2020-11-01
影响因子：
6.8
通讯作者：
Fang, Hezhi
中科院分区：
文献类型：
--
作者：
Du, Miaomiao;Wei, Xiujuan;Fang, Hezhi
目的：Leigh综合征(LS)是最常见的线粒体疾病之一，临床表现多样。然而，这种疾病的遗传变异谱并不完整。方法：使用下一代测序(NGS)来鉴定一例LS患者的m.14430A&Gt；G(p.W82R)变异。结果：患者NADH脱氢酶6(ND6)基因m.14430A>；G(p.W82R)突变显著高于其母亲。尽管基于传递线粒体Cybrid的研究表明m.14430G变异细胞的线粒体CI组装没有受到影响，但对照细胞的内源性和CI依赖的线粒体呼吸显著高于突变细胞。相应地，突变细胞的三磷酸腺苷、线粒体膜电位低于对照细胞，而胞外乳酸的产量高于对照细胞。值得注意的是，与野生型细胞相比，突变细胞在含半乳糖的培养液中的生长受到了损害。结论：从一名疑似LS的患者中发现了ND6基因的一个新的m.14430A>；G(p.W82R)变异，该变异通过降低线粒体CI的活性来损害线粒体的呼吸。
Objectives: Leigh syndrome (LS) is one of the most common mitochondrial diseases and has variable clinical symptoms. However, the genetic variant spectrum of this disease is incomplete.Methods: Next-generation sequencing (NGS) was used to identify the m.14430A > G (p.W82R) variant in a patient with LS. The pathogenesis of this novel complex I (CI) variant was verified by determining the mitochondrial respiration, assembly of CI, ATP, MMP and lactate production, and cell growth rate in cybrids with and without this variant.Results: A novel m.14430A > G (p.W82R) variant in the NADH dehydrogenase 6 (ND6) gene was identified in the patient; the mutant loads of m.14430A > G (p.W82R) in the patient were much higher than those in his mother. Although the transmitochondrial cybrid-based study showed that mitochondrial CI assembly remains unaffected in cells with the m.14430G variant, control cells had significantly higher endogenous and CI-dependent mitochondrial respiration than mutant cells. Accordingly, mutant cells had a lower ATP, MMP and higher extracellular lactate production than control cells. Notably, mutant cells had impaired growth in a galactose-containing medium when compared to wild-type cells.Conclusions: A novel m.14430A > G (p.W82R) variant in the ND6 gene was identified from a patient suspected to have LS, and this variant impaired mitochondrial respiration by decreasing the activity of mitochondrial CI.