PDF(Pubmed)
Abstract：
Mitochondrial complex V plays an important role in oxidative phosphorylation by catalyzing the generation of ATP. Most complex V subunits are nuclear encoded and not yet associated with recognized Mendelian disorders. Using exome sequencing, we identified a rare homozygous splice variant (c.87+3A>G) in ATP5PO, the complex V subunit which encodes the oligomycin sensitivity conferring protein, in three individuals from two unrelated families, with clinical suspicion of a mitochondrial disorder. These individuals had a similar, severe infantile and often lethal multi-systemic disorder that included hypotonia, developmental delay, hypertrophic cardiomyopathy, progressive epileptic encephalopathy, progressive cerebral atrophy, and white matter abnormalities on brain MRI consistent with Leigh syndrome. cDNA studies showed a predominant shortened transcript with skipping of exon 2 and low levels of the normal full-length transcript. Fibroblasts from the affected individuals demonstrated decreased ATP5PO protein, defective assembly of complex V with markedly reduced amounts of peripheral stalk proteins, and complex V hydrolytic activity. Further, expression of human ATP5PO cDNA without exon 2 (hATP5PO-∆ex2) in yeast cells deleted for yATP5 (ATP5PO homolog) was unable to rescue growth on media which requires oxidative phosphorylation when compared to the wild type construct (hATP5PO-WT), indicating that exon 2 deletion leads to a non-functional protein. Collectively, our findings support the pathogenicity of the ATP5PO c.87+3A>G variant, which significantly reduces but does not eliminate complex V activity. These data along with the recent report of an affected individual with ATP5PO variants, add to the evidence that rare biallelic variants in ATP5PO result in defective complex V assembly, function and are associated with Leigh syndrome.
摘要：
线粒体复合物V通过催化ATP的生成在氧化磷酸化中起重要作用。大多数复杂的V亚基是核编码的，尚未与公认的孟德尔障碍相关。使用外显子组测序，我们在ATP5PO中发现了一种罕见的纯合剪接变体（c.87+3A>G），编码寡霉素敏感性赋予蛋白的复杂V亚基，来自两个不相关家庭的三个人，临床怀疑线粒体疾病.这些人有类似的，严重的婴儿和通常致命的多系统疾病，包括张力减退，发育迟缓,肥厚型心肌病,进行性癫痫性脑病,进行性脑萎缩,脑MRI白质异常与Leigh综合征一致。cDNA研究显示具有外显子2的跳跃和低水平的正常全长转录物的主要缩短转录物。受影响个体的成纤维细胞显示ATP5PO蛋白降低，复合物V的组装缺陷，外周茎蛋白的数量显着减少，和复杂的V水解活性。Further,与野生型构建体（hATP5PO-WT）相比，缺失yATP5（ATP5PO同源物）的酵母细胞中无外显子2（hATP5PO-Δex2）的人ATP5POcDNA的表达无法在需要氧化磷酸化的培养基上挽救生长，表明外显子2缺失导致无功能蛋白。总的来说，我们的发现支持ATP5POc.87+3A>G变体的致病性，这显著降低但不消除复杂的V活性。这些数据以及最近的ATP5PO变种受影响个体的报告，增加ATP5PO中罕见的双等位基因变体导致有缺陷的复杂V组装的证据，功能，并与Leigh综合征有关。
