NDUFS6 mutations are a novel cause of lethal neonatal mitochondrial complex I deficiency
NDUFS6 mutations are a novel cause of lethal neonatal mitochondrial complex I deficiency
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DOI：
10.1172/jci200420683
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发表时间：
2004-09-01
影响因子：
15.9
通讯作者：
Thorburn, DR
中科院分区：
文献类型：
--
作者：
Kirby, DM;Salemi, R;Thorburn, DR
复合体I缺乏症是最常见的呼吸链缺陷，具有遗传异质性：编码复合体I亚单位的8个核和7个线粒体DNA基因突变已被描述。然而，这些基因只在少数复杂的I缺陷患者中导致了疾病。我们通过对10个无关患者的细胞系进行功能互补分析来研究是否可能存在未知的共同基因。其中两名患者被发现存在线粒体DNA突变。另外8个代表7个不同的(核)互补基团，除1个外，其余均显示复合体I组装异常。因此，任何一个未知基因都不太可能在复杂的i病例中占很大比例。核互补组的两名患者具有相似的异常复杂I组装图谱，并通过纯合子作图、染色体移植和微阵列表达分析进行了进一步研究。NDUFS6是一种复杂的I亚单位基因，以前并不与复杂的I缺乏症相关，它在2个患者细胞系中显著低表达。两名患者都有该基因的纯合子突变，一个导致了剪接异常，另一个导致了大的缺失。这种综合的基因识别方法为识别呼吸链疾病的其他未知原因提供了希望。
Complex I deficiency, the most common respiratory chain defect, is genetically heterogeneous: mutations in 8 nuclear and 7 mitochondrial DNA genes encoding complex I subunits have been described. However, these genes account for disease in only a minority of complex I-deficient patients. We investigated whether there may be an unknown common gene by performing functional complementation analysis of cell lines from 10 unrelated patients. Two of the patients were found to have mitochondrial DNA mutations. The other 8 represented 7 different (nuclear) complementation groups, all but 1 of which showed abnormalities of complex I assembly. It is thus unlikely that any one unknown gene accounts for a large proportion of complex I cases. The 2 patients sharing a nuclear complementation group had a similar abnormal complex I assembly profile and were studied further by homozygosity mapping, chromosome transfers, and microarray expression analysis. NDUFS6, a complex I subunit gene not previously associated with complex I deficiency, was grossly underexpressed in the 2 patient cell lines. Both patients had homozygous mutations in this gene, one causing a splicing abnormality and the other a large deletion. This integrated approach to gene identification offers promise for identifying other unknown causes of respiratory chain disorders.