Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1992 Jul;90(1):61–66. doi: 10.1172/JCI115856

Multiple deletions of mitochondrial DNA in several tissues of a patient with severe retarded depression and familial progressive external ophthalmoplegia.

A Suomalainen 1, A Majander 1, M Haltia 1, H Somer 1, J Lönnqvist 1, M L Savontaus 1, L Peltonen 1
PMCID: PMC443063  PMID: 1634620

Abstract

Multiple deletions of mitochondrial DNA (mtDNA) have recently been reported in familial progressive external ophthalmoplegia (PEO), in a case of progressive encephalomyopathy, and in inherited recurrent myoglobinuria. The inheritance of familial PEO has been autosomal dominant, which indicates that a mutation in an unknown nuclear gene results in several mtDNA deletions of different sizes in these patients. We report a patient with autosomal dominant PEO, whose major clinical symptom, however, was severe retarded depression. The morphological analyses of the tissue samples derived from autopsy showed various abnormalities in the mitochondria in all the tissues studied. The activities of the respiratory chain enzymes encoded by mtDNA were remarkably reduced in the skeletal muscle. The mtDNA analyses confirmed that besides myopathy, this patient had a multisystem disorder with widespread distribution of multiple deletions of mtDNA. The highest percentage of mutated mtDNA was found in the brain, skeletal muscle and the heart, the relative quantity of mutated mtDNA correlating to the severity of the clinical symptoms.

Full text

PDF
61

Images in this article

62Image
on p.62
62Image
on p.62
63Image
on p.63
64Image
on p.64

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ackrell B. A., Kearney E. B., Singer T. P. Mammalian succinate dehydrogenase. Methods Enzymol. 1978;53:466–483. doi: 10.1016/s0076-6879(78)53050-4. [DOI] [PubMed] [Google Scholar]
  2. Anderson S., Bankier A. T., Barrell B. G., de Bruijn M. H., Coulson A. R., Drouin J., Eperon I. C., Nierlich D. P., Roe B. A., Sanger F. Sequence and organization of the human mitochondrial genome. Nature. 1981 Apr 9;290(5806):457–465. doi: 10.1038/290457a0. [DOI] [PubMed] [Google Scholar]
  3. Bookelman H., Trijbels J. M., Sengers R. C., Janssen A. J., Veerkamp J. H., Stadhouders A. M. Pyruvate oxidation in rat and human skeletal muscle mitochondria. Biochem Med. 1978 Dec;20(3):395–403. doi: 10.1016/0006-2944(78)90089-3. [DOI] [PubMed] [Google Scholar]
  4. Clayton D. A. Replication of animal mitochondrial DNA. Cell. 1982 Apr;28(4):693–705. doi: 10.1016/0092-8674(82)90049-6. [DOI] [PubMed] [Google Scholar]
  5. Cormier V., Rotig A., Tardieu M., Colonna M., Saudubray J. M., Munnich A. Autosomal dominant deletions of the mitochondrial genome in a case of progressive encephalomyopathy. Am J Hum Genet. 1991 Apr;48(4):643–648. [PMC free article] [PubMed] [Google Scholar]
  6. Cortopassi G. A., Arnheim N. Detection of a specific mitochondrial DNA deletion in tissues of older humans. Nucleic Acids Res. 1990 Dec 11;18(23):6927–6933. doi: 10.1093/nar/18.23.6927. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Feinberg A. P., Vogelstein B. "A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity". Addendum. Anal Biochem. 1984 Feb;137(1):266–267. doi: 10.1016/0003-2697(84)90381-6. [DOI] [PubMed] [Google Scholar]
  8. Fischer J. C., Ruitenbeek W., Berden J. A., Trijbels J. M., Veerkamp J. H., Stadhouders A. M., Sengers R. C., Janssen A. J. Differential investigation of the capacity of succinate oxidation in human skeletal muscle. Clin Chim Acta. 1985 Nov 29;153(1):23–36. doi: 10.1016/0009-8981(85)90135-4. [DOI] [PubMed] [Google Scholar]
  9. Holt I. J., Harding A. E., Morgan-Hughes J. A. Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature. 1988 Feb 25;331(6158):717–719. doi: 10.1038/331717a0. [DOI] [PubMed] [Google Scholar]
  10. Johns D. R., Rutledge S. L., Stine O. C., Hurko O. Directly repeated sequences associated with pathogenic mitochondrial DNA deletions. Proc Natl Acad Sci U S A. 1989 Oct;86(20):8059–8062. doi: 10.1073/pnas.86.20.8059. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Mita S., Rizzuto R., Moraes C. T., Shanske S., Arnaudo E., Fabrizi G. M., Koga Y., DiMauro S., Schon E. A. Recombination via flanking direct repeats is a major cause of large-scale deletions of human mitochondrial DNA. Nucleic Acids Res. 1990 Feb 11;18(3):561–567. doi: 10.1093/nar/18.3.561. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Moraes C. T., DiMauro S., Zeviani M., Lombes A., Shanske S., Miranda A. F., Nakase H., Bonilla E., Werneck L. C., Servidei S. Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre syndrome. N Engl J Med. 1989 May 18;320(20):1293–1299. doi: 10.1056/NEJM198905183202001. [DOI] [PubMed] [Google Scholar]
  13. Ohno K., Tanaka M., Sahashi K., Ibi T., Sato W., Yamamoto T., Takahashi A., Ozawa T. Mitochondrial DNA deletions in inherited recurrent myoglobinuria. Ann Neurol. 1991 Apr;29(4):364–369. doi: 10.1002/ana.410290406. [DOI] [PubMed] [Google Scholar]
  14. Ozawa T., Yoneda M., Tanaka M., Ohno K., Sato W., Suzuki H., Nishikimi M., Yamamoto M., Nonaka I., Horai S. Maternal inheritance of deleted mitochondrial DNA in a family with mitochondrial myopathy. Biochem Biophys Res Commun. 1988 Aug 15;154(3):1240–1247. doi: 10.1016/0006-291x(88)90272-0. [DOI] [PubMed] [Google Scholar]
  15. Poulton J., Deadman M. E., Ramacharan S., Gardiner R. M. Germ-line deletions of mtDNA in mitochondrial myopathy. Am J Hum Genet. 1991 Apr;48(4):649–653. [PMC free article] [PubMed] [Google Scholar]
  16. Rotig A., Colonna M., Bonnefont J. P., Blanche S., Fischer A., Saudubray J. M., Munnich A. Mitochondrial DNA deletion in Pearson's marrow/pancreas syndrome. Lancet. 1989 Apr 22;1(8643):902–903. doi: 10.1016/s0140-6736(89)92897-3. [DOI] [PubMed] [Google Scholar]
  17. Saiki R. K., Gelfand D. H., Stoffel S., Scharf S. J., Higuchi R., Horn G. T., Mullis K. B., Erlich H. A. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science. 1988 Jan 29;239(4839):487–491. doi: 10.1126/science.2448875. [DOI] [PubMed] [Google Scholar]
  18. Schon E. A., Rizzuto R., Moraes C. T., 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. doi: 10.1126/science.2711184. [DOI] [PubMed] [Google Scholar]
  19. Servidei S., Zeviani M., Manfredi G., Ricci E., Silvestri G., Bertini E., Gellera C., Di Mauro S., Di Donato S., Tonali P. Dominantly inherited mitochondrial myopathy with multiple deletions of mitochondrial DNA: clinical, morphologic, and biochemical studies. Neurology. 1991 Jul;41(7):1053–1059. doi: 10.1212/wnl.41.7.1053. [DOI] [PubMed] [Google Scholar]
  20. Shoffner J. M., Lott M. T., Voljavec A. S., Soueidan S. A., Costigan D. A., Wallace D. C. Spontaneous Kearns-Sayre/chronic external ophthalmoplegia plus syndrome associated with a mitochondrial DNA deletion: a slip-replication model and metabolic therapy. Proc Natl Acad Sci U S A. 1989 Oct;86(20):7952–7956. doi: 10.1073/pnas.86.20.7952. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Southern E. M. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol. 1975 Nov 5;98(3):503–517. doi: 10.1016/s0022-2836(75)80083-0. [DOI] [PubMed] [Google Scholar]
  22. Yuzaki M., Ohkoshi N., Kanazawa I., Kagawa Y., Ohta S. Multiple deletions in mitochondrial DNA at direct repeats of non-D-loop regions in cases of familial mitochondrial myopathy. Biochem Biophys Res Commun. 1989 Nov 15;164(3):1352–1357. doi: 10.1016/0006-291x(89)91818-4. [DOI] [PubMed] [Google Scholar]
  23. Zeviani M., Bresolin N., Gellera C., Bordoni A., Pannacci M., Amati P., Moggio M., Servidei S., Scarlato G., DiDonato S. Nucleus-driven multiple large-scale deletions of the human mitochondrial genome: a new autosomal dominant disease. Am J Hum Genet. 1990 Dec;47(6):904–914. [PMC free article] [PubMed] [Google Scholar]
  24. Zeviani M., Moraes C. T., DiMauro S., Nakase H., Bonilla E., Schon E. A., Rowland L. P. Deletions of mitochondrial DNA in Kearns-Sayre syndrome. Neurology. 1988 Sep;38(9):1339–1346. doi: 10.1212/wnl.38.9.1339. [DOI] [PubMed] [Google Scholar]
  25. Zeviani M., Servidei S., Gellera C., Bertini E., DiMauro S., DiDonato S. An autosomal dominant disorder with multiple deletions of mitochondrial DNA starting at the D-loop region. Nature. 1989 May 25;339(6222):309–311. doi: 10.1038/339309a0. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES