Petruzzella V, Moraes C T, Sano M C, Bonilla E, DiMauro S, Schon E A
Department of Neurology, Columbia University College of Physicians & Surgeons, New York, NY 10032.
Hum Mol Genet. 1994 Mar;3(3):449-54. doi: 10.1093/hmg/3.3.449.
A single mtDNA point mutation at nt 3243 has been associated with two different clinical phenotypes: mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes ('MELAS3243') and progressive external ophthalmoplegia ('PEO3243'). It has been shown that there is a much higher proportion of ragged-red fibers (RRF) with cytochrome c oxidase (COX) deficiency in PEO3243 than in MELAS3243. Using PCR/RFLP analysis of isolated individual skeletal muscle fibers from patients with both syndromes, we found a direct correlation between the localized concentration of the nt 3243 mutation and impairment of COX function at the single muscle fiber level: we found relatively low levels of mutant mtDNAs (56 +/- 21%) in 'normal' fibers; high levels (90 +/- 6%) in COX-positive RRF; and an almost complete segregation of mutant mtDNAs (95 +/- 3%) in COX-negative RRF. Thus, the differential distribution of fibers with extremely high concentrations of mutant mtDNAs characterizes, and probably distinguishes, the skeletal muscle of PEO and MELAS patients harboring the same nt-3243 mutation.
线粒体DNA（mtDNA）第3243位核苷酸处的单个点突变与两种不同的临床表型相关：线粒体脑肌病伴乳酸酸中毒和卒中样发作（“MELAS3243”）以及进行性眼外肌麻痹（“PEO3243”）。研究表明，PEO3243中细胞色素c氧化酶（COX）缺乏的破碎红纤维（RRF）比例远高于MELAS3243。通过对这两种综合征患者分离出的单个骨骼肌纤维进行聚合酶链反应/限制性片段长度多态性（PCR/RFLP）分析，我们发现在单根肌纤维水平上，第3243位核苷酸突变的局部浓度与COX功能受损之间存在直接关联：我们在“正常”纤维中发现相对较低水平的突变型mtDNA（56±21%）；在COX阳性的RRF中水平较高（90±6%）；而在COX阴性的RRF中突变型mtDNA几乎完全分离（95±3%）。因此，具有极高浓度突变型mtDNA的纤维的差异分布是携带相同第3243位核苷酸突变的PEO和MELAS患者骨骼肌的特征，并且可能是区分两者的依据。
