Large-scale deletion and point mutations of the nuclear NDUFV1 and NDUFS1 genes in mitochondrial complex I deficiency
Large-scale deletion and point mutations of the nuclear NDUFV1 and NDUFS1 genes in mitochondrial complex I deficiency
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DOI：
10.1086/320603
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发表时间：
2001-06-01
影响因子：
9.8
通讯作者：
Rötig, A
中科院分区：
文献类型：
--
作者：
Bénit, P;Chretien, D;Rötig, A
还原型烟酰胺腺嘌呤二核苷酸（NADH）：泛醌氧化还原酶（复合物I）是线粒体呼吸链中最大的复合物，复合物I缺乏症占人类呼吸链缺乏症的30%。只有7个线粒体DNA基因，但>35个核基因编码复合物I亚基。为了阐明复合物I缺陷的分子基础，我们研究了6个最保守的复合物I核基因（NDUFV 1，NDUFS 8，NDUFS 7，NDUFS 1，NDUFA 8和NDUFB 6）在一系列的36例患者与分离的复合物I缺陷通过变性高效液相色谱和直接测序相应的cDNA从培养的皮肤成纤维细胞。在3/36例患者中，我们首次确定了NDUFS 1基因的5个点突变（del 222、D252 G、M707 V、R241 W和R557 X）和1个大规模缺失。此外，我们在另外3名患者中发现了6个新的NDUFV 1突变（Y204 C、C206 G、E214 K、IVS 8+41、A432 P和del nt 989-990）。6名无关患者表现为肌张力减退、共济失调、精神发育迟滞或Leigh综合征。这些结果表明，筛选复合物I核基因突变是特别感兴趣的患者与复合物I缺乏症，即使在正常的代谢链酶活性培养的成纤维细胞观察。
Reduced nicotinamide adenine dinucleotide (NADH): ubiquinone oxidoreductase (complex I) is the largest complex of the mitochondrial respiratory chain and complex I deficiency accounts for similar to 30% cases of respiratory-chain deficiency in humans. Only seven mitochondrial DNA genes, but >35 nuclear genes encode complex I subunits. In an attempt to elucidate the molecular bases of complex I deficiency, we studied the six most-conserved complex I nuclear genes (NDUFV1, NDUFS8, NDUFS7, NDUFS1, NDUFA8, and NDUFB6) in a series of 36 patients with isolated complex I deficiency by denaturing high-performance liquid chromatography and by direct sequencing of the corresponding cDNA from cultured skin fibroblasts. In 3/36 patients, we identified, for the first time, five point mutations (del222, D252G, M707V, R241W, and R557X) and one large-scale deletion in the NDUFS1 gene. In addition, we found six novel NDUFV1 mutations (Y204C, C206G, E214K, IVS 8+41, A432P, and del nt 989-990) in three other patients. The six unrelated patients presented with hypotonia, ataxia, psychomotor retardation, or Leigh syndrome. These results suggest that screening for complex I nuclear gene mutations is of particular interest in patients with complex I deficiency, even when normal respiratory-chain-enzyme activities in cultured fibroblasts are observed.