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Am J Hum Genet. 1990 Mar; 46(3): 418–427.
PMCID: PMC1683616

Transcription and translation of deleted mitochondrial genomes in Kearns-Sayre syndrome: implications for pathogenesis.


Large-scale deletions of human mitochondrial DNA (mtDNA) have been described in a clinical subgroup of mitochondrial encephalomyopathies associated with progressive external ophthalmoplegia and ragged-red fibers in skeletal muscle, including cases of Kearns-Sayre syndrome (KSS). Since the decrease in the activities of mtDNA-encoded respiratory-chain enzymes did not seem to be correlated to the sites of the deletions, the role played by the mtDNA deletions in the pathogenesis of these disorders has been unclear. To address this issue, we studied transcription and translation of deleted mtDNA in two patients with KSS harboring two different deletions. We found that the deleted genomes were transcriptionally active in both cases. Analysis of translation in one of the patients showed that the "fusion" mRNA derived from the region spanning the deletion did not seem to be translated. Thus, the biochemical defects in KSS can be explained by a lack of translation of mtDNA-encoded respiratory-chain polypeptides in some mitochondria, which, in turn, is probably due to the lack of indispensable mtDNA-encoded tRNAs in these organelles. These results imply that deleted mtDNAs may be segregated from normal genomes in this group of diseases. It seems likely that the absence of translation in proliferating mitochondria containing partially deleted genomes plays a major role in the pathogenesis of these disorders.

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  • Adoutte A, Sainsard A, Rossignol M, Beisson J. Aspects génétiques de la biogenèse des mitochondries chez la Paramécie. Biochimie. 1973;55(6):793–799. [PubMed]
  • Anderson S, Bankier AT, Barrell BG, de Bruijn MH, Coulson AR, Drouin J, Eperon IC, Nierlich DP, Roe BA, Sanger F, et al. Sequence and organization of the human mitochondrial genome. Nature. 1981 Apr 9;290(5806):457–465. [PubMed]
  • Ashley MV, Laipis PJ, Hauswirth WW. Rapid segregation of heteroplasmic bovine mitochondria. Nucleic Acids Res. 1989 Sep 25;17(18):7325–7331. [PMC free article] [PubMed]
  • Bertrand H, Chan BS, Griffiths AJ. Insertion of a foreign nucleotide sequence into mitochondrial DNA causes senescence in Neurospora intermedia. Cell. 1985 Jul;41(3):877–884. [PubMed]
  • Bertrand H, Griffiths AJ, Court DA, Cheng CK. An extrachromosomal plasmid is the etiological precursor of kalDNA insertion sequences in the mitochondrial chromosome of senescent neurospora. Cell. 1986 Dec 5;47(5):829–837. [PubMed]
  • Boutry M, Nagy F, Poulsen C, Aoyagi K, Chua NH. Targeting of bacterial chloramphenicol acetyltransferase to mitochondria in transgenic plants. Nature. 1987 Jul 23;328(6128):340–342. [PubMed]
  • Burnett KG, Scheffler IE. Integrity of mitochondria in a mammalian cell mutant defective in mitochondrial protein synthesis. J Cell Biol. 1981 Jul;90(1):108–115. [PMC free article] [PubMed]
  • Chomyn A, Cleeter MW, Ragan CI, Riley M, Doolittle RF, Attardi G. URF6, last unidentified reading frame of human mtDNA, codes for an NADH dehydrogenase subunit. Science. 1986 Oct 31;234(4776):614–618. [PubMed]
  • Church GM, Gilbert W. Genomic sequencing. Proc Natl Acad Sci U S A. 1984 Apr;81(7):1991–1995. [PMC free article] [PubMed]
  • Clark-Walker GD, Miklos GL. Complementation in cytoplasmic petite mutants of yeast to form respiratory competent cells. Proc Natl Acad Sci U S A. 1975 Jan;72(1):372–375. [PMC free article] [PubMed]
  • Ditta G, Soderberg K, Scheffler IE. Chinese hamster cell mutant with defective mitochondrial protein synthesis. Nature. 1977 Jul 7;268(5615):64–67. [PubMed]
  • Emr SD, Vassarotti A, Garrett J, Geller BL, Takeda M, Douglas MG. The amino terminus of the yeast F1-ATPase beta-subunit precursor functions as a mitochondrial import signal. J Cell Biol. 1986 Feb;102(2):523–533. [PMC free article] [PubMed]
  • Feinberg AP, Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. [PubMed]
  • Hayashi J, Tagashira Y, Yoshida MC. Absence of extensive recombination between inter- and intraspecies mitochondrial DNA in mammalian cells. Exp Cell Res. 1985 Oct;160(2):387–395. [PubMed]
  • Hayashi J, Werbin H, Shay JW. Effects of normal human fibroblast mitochondrial DNA on segregation of HeLaTG Mitochondrial DNA and on tumorigenicity of HeLaTG cells. Cancer Res. 1986 Aug;46(8):4001–4006. [PubMed]
  • Holt IJ, Harding AE, Morgan-Hughes JA. Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature. 1988 Feb 25;331(6158):717–719. [PubMed]
  • Hurt EC, Pesold-Hurt B, Schatz G. The amino-terminal region of an imported mitochondrial precursor polypeptide can direct cytoplasmic dihydrofolate reductase into the mitochondrial matrix. EMBO J. 1984 Dec 20;3(13):3149–3156. [PMC free article] [PubMed]
  • King MP, Attardi G. Injection of mitochondria into human cells leads to a rapid replacement of the endogenous mitochondrial DNA. Cell. 1988 Mar 25;52(6):811–819. [PubMed]
  • Lehrach H, Diamond D, Wozney JM, Boedtker H. RNA molecular weight determinations by gel electrophoresis under denaturing conditions, a critical reexamination. Biochemistry. 1977 Oct 18;16(21):4743–4751. [PubMed]
  • Mariottini P, Chomyn A, Riley M, Cottrell B, Doolittle RF, Attardi G. Identification of the polypeptides encoded in the unassigned reading frames 2, 4, 4L, and 5 of human mitochondrial DNA. Proc Natl Acad Sci U S A. 1986 Mar;83(6):1563–1567. [PMC free article] [PubMed]
  • Merle P, Kadenbach B. The subunit composition of mammalian cytochrome c oxidase. Eur J Biochem. 1980 Apr;105(3):499–507. [PubMed]
  • Mita S, Schmidt B, Schon EA, DiMauro S, Bonilla E. Detection of "deleted" mitochondrial genomes in cytochrome-c oxidase-deficient muscle fibers of a patient with Kearns-Sayre syndrome. Proc Natl Acad Sci U S A. 1989 Dec;86(23):9509–9513. [PMC free article] [PubMed]
  • Moraes CT, DiMauro S, Zeviani M, Lombes A, Shanske S, Miranda AF, Nakase H, Bonilla E, Werneck LC, Servidei S, et al. Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre syndrome. N Engl J Med. 1989 May 18;320(20):1293–1299. [PubMed]
  • Moraes CT, Schon EA, DiMauro S, Miranda AF. Heteroplasmy of mitochondrial genomes in clonal cultures from patients with Kearns-Sayre syndrome. Biochem Biophys Res Commun. 1989 Apr 28;160(2):765–771. [PubMed]
  • Morgens PH, Grabau EA, Gesteland RF. A novel soybean mitochondrial transcript resulting from a DNA rearrangement involving the 5S rRNA gene. Nucleic Acids Res. 1984 Jul 25;12(14):5665–5684. [PMC free article] [PubMed]
  • Ojala D, Montoya J, Attardi G. tRNA punctuation model of RNA processing in human mitochondria. Nature. 1981 Apr 9;290(5806):470–474. [PubMed]
  • Oliver NA, Wallace DC. Assignment of two mitochondrially synthesized polypeptides to human mitochondrial DNA and their use in the study of intracellular mitochondrial interaction. Mol Cell Biol. 1982 Jan;2(1):30–41. [PMC free article] [PubMed]
  • Olivo PD, Van de Walle MJ, Laipis PJ, Hauswirth WW. Nucleotide sequence evidence for rapid genotypic shifts in the bovine mitochondrial DNA D-loop. Nature. 1983 Nov 24;306(5941):400–402. [PubMed]
  • Palva TK, Palva ET. Rapid isolation of animal mitochondrial DNA by alkaline extraction. FEBS Lett. 1985 Nov 18;192(2):267–270. [PubMed]
  • Saiki RK, Scharf S, Faloona F, Mullis KB, Horn GT, Erlich HA, Arnheim N. Enzymatic amplification of beta-globin genomic sequences and restriction site analysis for diagnosis of sickle cell anemia. Science. 1985 Dec 20;230(4732):1350–1354. [PubMed]
  • Schon EA, Rizzuto R, Moraes CT, Nakase H, Zeviani M, DiMauro S. A direct repeat is a hotspot for large-scale deletion of human mitochondrial DNA. Science. 1989 Apr 21;244(4902):346–349. [PubMed]
  • Ullrich A, Shine J, Chirgwin J, Pictet R, Tischer E, Rutter WJ, Goodman HM. Rat insulin genes: construction of plasmids containing the coding sequences. Science. 1977 Jun 17;196(4296):1313–1319. [PubMed]
  • Wallace DC, Singh G, Lott MT, Hodge JA, Schurr TG, Lezza AM, Elsas LJ, 2nd, Nikoskelainen EK. Mitochondrial DNA mutation associated with Leber's hereditary optic neuropathy. Science. 1988 Dec 9;242(4884):1427–1430. [PubMed]
  • White FA, Bunn CL. Segregation of mitochondrial DNA in human somatic cell hybrids. Mol Gen Genet. 1984;197(3):453–460. [PubMed]
  • Wilson GN, Hollar BA, Waterson JR, Schmickel RD. Molecular analysis of cloned human 18S ribosomal DNA segments. Proc Natl Acad Sci U S A. 1978 Nov;75(11):5367–5371. [PMC free article] [PubMed]
  • Wrischnik LA, Higuchi RG, Stoneking M, Erlich HA, Arnheim N, Wilson AC. Length mutations in human mitochondrial DNA: direct sequencing of enzymatically amplified DNA. Nucleic Acids Res. 1987 Jan 26;15(2):529–542. [PMC free article] [PubMed]
  • Zeviani M, Moraes CT, DiMauro S, Nakase H, Bonilla E, Schon EA, Rowland LP. Deletions of mitochondrial DNA in Kearns-Sayre syndrome. Neurology. 1988 Sep;38(9):1339–1346. [PubMed]

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