Comi G P, Bordoni A, Salani S, Franceschina L, Sciacco M, Prelle A, Fortunato F, Zeviani M, Napoli L, Bresolin N, Moggio M, Ausenda C D, Taanman J W, Scarlato G
Centro Dino Ferrari, Universita' degli Studi di Milano, IRCCS Ospedale Maggiore Policlinico, Milan, Italy.
Ann Neurol. 1998 Jan;43(1):110-6. doi: 10.1002/ana.410430119.
An out-of-frame mutation of the mitochondrial DNA-encoded subunit I of cytochrome c oxidase (COX) was discovered during investigation of a severe isolated muscle COX deficiency in a patient with motor neuron-like degeneration. The mutation is a heteroplasmic 5-bp microdeletion located in the 5' end of the COI gene, leading to premature termination of the corresponding translation product. Western blot analysis, immunohistochemistry, and single-fiber polymerase chain reaction demonstrated a tight correlation between COX defect, COX I expression, and percentage of mutation. COX subunits II, III, and IV were decreased as well, suggesting a defective assembly of COX holoenzyme. The mutation was associated with a clinical phenotype unusual for a mitochondrial disorder, that is, an isolated motor neuron disease (MND) with some atypical findings, including early onset, preferential involvement of the upper motor neuron, and increased cerebrospinal fluid protein content. MND may arise from impaired scavenging and overproduction of free oxygen radicals, a by-product of oxidative phosphorylation (OXPHOS). Our observation suggests that OXPHOS impairment could play a role in the pathogenesis of some MND cases.
在对一名患有运动神经元样变性的严重孤立性肌肉细胞色素 c 氧化酶（COX）缺乏症患者进行调查时，发现了线粒体 DNA 编码的细胞色素 c 氧化酶亚基 I 的框外突变。该突变是位于 COI 基因 5' 端的一个异质性 5 碱基微缺失，导致相应翻译产物提前终止。蛋白质免疫印迹分析、免疫组织化学和单纤维聚合酶链反应表明，COX 缺陷、COX I 表达与突变百分比之间存在紧密相关性。COX 亚基 II、III 和 IV 也减少，提示 COX 全酶组装存在缺陷。该突变与线粒体疾病不常见的临床表型相关，即一种具有一些非典型表现的孤立性运动神经元疾病（MND），包括发病早、上运动神经元优先受累以及脑脊液蛋白含量增加。MND 可能源于氧化磷酸化（OXPHOS）副产物——游离氧自由基的清除受损和过量产生。我们的观察结果表明，OXPHOS 损伤可能在某些 MND 病例的发病机制中起作用。
