Hinttala R, Smeets R, Moilanen J S, Ugalde C, Uusimaa J, Smeitink J A M, Majamaa K
J Med Genet. 2006 Nov;43(11):881-6. doi: 10.1136/jmg.2006.042168. Epub 2006 May 31.
Enzyme deficiencies of the oxidative phosphorylation (OXPHOS) system may be caused by mutations in the mitochondrial DNA (mtDNA) or in the nuclear DNA.
To analyse the sequences of the mtDNA coding region in 25 patients with OXPHOS system deficiency to identify the underlying genetic defect.
Three novel non-synonymous substitutions in protein-coding genes, 4681T-->C in MT-ND2, 9891T-->C in MT-CO3 and 14122A-->G in MT-ND5, and one novel substitution in the 12S rRNA gene, 686A-->G, were found. The definitely pathogenic mutation 3460G-->A was identified in an 18-year-old woman who had severe isolated complex I deficiency and progressive myopathy.
Bioinformatic analyses suggest a pathogenic role for the novel 4681T-->C substitution found in a boy with Leigh's disease. These results show that the clinical phenotype caused by the primary Leber's hereditary optic neuropathy mutation 3460G-->A is more variable than has been thought. In the remaining 23 patients, the role of mtDNA mutations as a cause of the OXPHOS system deficiency could be excluded. The deficiency in these children probably originates from mutations in the nuclear genes coding for respiratory enzyme subunits or assembly factors.
氧化磷酸化（OXPHOS）系统的酶缺陷可能由线粒体DNA（mtDNA）或核DNA中的突变引起。
分析25例氧化磷酸化系统缺陷患者的mtDNA编码区序列，以确定潜在的基因缺陷。
在蛋白编码基因中发现了三个新的非同义替换，分别是MT-ND2基因中的4681T→C、MT-CO3基因中的9891T→C和MT-ND5基因中的14122A→G，以及12S rRNA基因中的一个新替换686A→G。在一名患有严重孤立性复合体I缺陷和进行性肌病的18岁女性中鉴定出明确的致病性突变3460G→A。
生物信息学分析表明，在一名患有 Leigh 病的男孩中发现的新的4681T→C替换具有致病作用。这些结果表明，原发性Leber遗传性视神经病变突变3460G→A所导致的临床表型比之前认为的更具变异性。在其余23例患者中，可以排除mtDNA突变作为氧化磷酸化系统缺陷原因的可能性。这些儿童的缺陷可能源于编码呼吸酶亚基或装配因子的核基因中的突变。
