Wittig I, Augstein P, Brown G K, Fujii T, Rötig A, Rustin P, Munnich A, Seibel P, Thorburn D, Wissinger B, Tamboom K, Metspalu A, Lamantea E, Zeviani M, Wehnert M S
Institute of Human Genetics, Greifswald, Germany.
J Inherit Metab Dis. 2001 Feb;24(1):15-27. doi: 10.1023/a:1005638218246.
NDUFA1 is one of the 36 nuclear genes encoding subunits of the mitochondrial complex I involved in the respiratory chain. The human NDUFA1 has been cloned, completely sequenced and mapped to Xq24. In the present study, we searched for sequence variations in NDUFA1 as causative defects in complex I deficiency using genomic DNA of 152 patients with various clinical phenotypes. The patient sample consisted of 54 patients (46 male and 8 female) with Leber heriditary optic neuropathy (LHON) from 48 unrelated families from Germany and 98 patients (72 male and 26 female) with biochemically proven complex I deficiency including Leigh syndrome. Patient DNA was used to amplify all three exons, including the exon/intron boundaries and the promoter region of NDUFA1 for heteroduplex analysis and direct sequencing. In the 152 patients tested, no mutation was found that could be related to any of the disease phenotypes included. However, three single-nucleotide polymorphisms (SNPs) located in the promoter region (SNP G/C at nt -71 and SNP T/C at nt -189) and in intron 1 (SNP T/G nt 1454) were discovered. Allele frequencies of the SNPs were estimated in a German and Estonian control population and compared to complex I-deficient patients. There was no significant difference between the control population, the LHON patients, or the severely affected patients with complex I deficiency, excluding an association of the polymorphisms with the diseases. Our results suggest that mutations in NDUFA1 do not cause the gender difference observed in clinically severe and complex phenotypes with complex I deficiency.
NDUFA1是36个编码参与呼吸链的线粒体复合物I亚基的核基因之一。人类NDUFA1已被克隆、完全测序并定位到Xq24。在本研究中，我们使用152例具有各种临床表型的患者的基因组DNA，搜索NDUFA1中的序列变异，作为复合物I缺乏症的致病缺陷。患者样本包括来自德国48个无关家庭的54例（46例男性和8例女性）患有Leber遗传性视神经病变（LHON）的患者，以及98例（72例男性和26例女性）经生化证实患有复合物I缺乏症（包括Leigh综合征）的患者。使用患者DNA扩增所有三个外显子，包括NDUFA1的外显子/内含子边界和启动子区域，用于异源双链分析和直接测序。在测试的152例患者中，未发现与所包括的任何疾病表型相关的突变。然而，发现了位于启动子区域（nt -71处的SNP G/C和nt -189处的SNP T/C）和内含子1（nt 1454处的SNP T/G）的三个单核苷酸多态性（SNP）。在德国和爱沙尼亚的对照人群中估计了这些SNP的等位基因频率，并与复合物I缺乏症患者进行了比较。对照人群、LHON患者或患有严重复合物I缺乏症的患者之间没有显著差异，排除了这些多态性与疾病的关联。我们的结果表明，NDUFA1中的突变不会导致在临床上严重的复合物I缺乏症复杂表型中观察到的性别差异。
