Large-scale deletions of mitochondrial DNA (mtDNA) have been described in patients with progressive external ophthalmoplegia (PEO) and ragged red fibers. We have determined the exact deletion breakpoint in 28 cases with PEO, including 12 patients already shown to harbor an identical deletion; the other patients had 16 different deletions. The deletions fell into two classes. In Class I (9 deletions; 71% of the patients), the deletion was flanked by perfect direct repeats, located (in normal mtDNA) at the edges of the deletion. In Class II (8 deletions; 29% of patients), the deletions were not flanked by any obviously unique repeat element, or they were flanked by repeat elements which were located imprecisely relative to the breakpoints. Computer analysis showed a correlation between the location of the deletion breakpoints and sequences in human mtDNA similar to the target sequence for Drosophila topoisomerase II. It is not known how these deletions originate, but both slipped mispairing and legitimate recombination could be mechanisms playing a major role in the generation of the large mtDNA deletions found in PEO.
We have studied five children with mitochondrial myopathy manifesting within or soon after the first year of life. Muscle biopsies showed ragged-red fibers and decreased respiratory chain activity. All five patients had a severe decrease (2 to 34% of normal) in the amount of muscle mitochondrial DNA (mtDNA). The depletion of mtDNA correlated with absence of mtDNA-encoded translation products and with loss of cytochrome c oxidase enzyme activity in individual muscle fibers. This mitochondrial myopathy of childhood illustrates one phenotypic expression of a novel pathogenetic mechanism in mitochondrial diseases, the specific depletion of mtDNA in affected tissues.
We identified large-scale heteroplasmic mitochondrial DNA (mtDNA) rearrangements in a 50-year-old woman with an adult-onset progressive myopathy. The predominant mtDNA abnormality was a 21.2-kb duplicated molecule. In addition, a small population of the corresponding partially deleted 4.6-kb molecule was detected. Skeletal muscle histology revealed fibers that were negative for cytochrome c oxidase (COX) activity and had reduced mtDNA-encoded COX subunits. By single-fiber polymerase chain reaction analysis, COX-negative fibers contained a low number of wild-type or duplicated mtDNA molecules (ie, nondeleted). In situ hybridization demonstrated that the abnormal fibers contained increased amounts of mtDNA compared with normal fibers and that most of the genomes were deleted. We concluded that deleted mtDNA molecules were primarily responsible for the phenotype in this patient.
Cytochrcae c cxcidase (COX; EC 1.9.3.1) catalyzes the transfer of electrons fra reduced cytochran c to uolecular aoygen in the mitochdrial respirtory diain. In mmnamls, the apoprotein is ccmposed of three larger catalytic suimits, encoded by the tc ria genrupx, and by ten smaller, nmclear-e ded submnits, which may play a reulatory role (1); subunits VIa, VIIa, and VIII have been shown to have heart-and liver-specific isoforms in cows and pigs (2), and c[s encoding the heart-and liver-specific isoforms of sub.unit VIa have been isolated fram rat (3). Usirq a rat liver COX VIa cDEA (3) as a prcbe, we isolated a partial-length clone frQa human liver cIA library (a gift of G. Ricca, Meloy labratories), and a full-length clone (pCOX6a.24; sequenCe below) frcm a human er ial cell cIlI library (a gift of M. Chao arxi D. Littman). Ihe de polypeptide is 87% idntical to rat liver COX VIa, but only 51% identical to rat heart O)X VIa (3). Like rat heart C)X VIa aid VIc (4), human liver COX VIa does not contain an in-frame cleavable presequence for inportation into mitocaondria.[5' EcoRI linker] TI'IITITITTAGAAGAAATkAAMlrGr (30) AGlllululll G (90)
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