Fatal infantile cardioencephalomyopathy with COX deficiency and mutations in SCO2, a COX assembly gene (original) (raw)

Nature Genetics volume 23, pages 333–337 (1999) Cite this article

Abstract

Mammalian cytochrome c oxidase (COX) catalyses the transfer of reducing equivalents from cytochrome c to molecular oxygen and pumps protons across the inner mitochondrial membrane1. Mitochondrial DNA (mtDNA) encodes three COX subunits (I–III) and nuclear DNA (nDNA) encodes ten. In addition, ancillary proteins are required for the correct assembly and function of COX (refs 2, 3, 4, 5, 6). Although pathogenic mutations in mtDNA-encoded COX subunits have been described7, no mutations in the nDNA-encoded subunits have been uncovered in any mendelian-inherited COX deficiency disorder8,9,10,11,12,13. In yeast, two related COX assembly genes, SCO1 and SCO2 (for synthesis of cytochrome c oxidase), enable subunits I and II to be incorporated into the holoprotein. Here we have identified mutations in the human homologue, SCO2, in three unrelated infants with a newly recognized fatal cardioencephalomyopathy and COX deficiency. Immunohistochemical studies implied that the enzymatic deficiency, which was most severe in cardiac and skeletal muscle, was due to the loss of mtDNA-encoded COX subunits. The clinical phenotype caused by mutations in human SCO2 differs from that caused by mutations in SURF1, the only other known COX assembly gene associated with a human disease, Leigh syndrome14,15.

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Acknowledgements

We thank F. Guo, P. Kranz-Eberle, F. Pallotti, P. Magalhães, G. Manfredi, R. Pons and S. Tadesse for technical assistance; E. Holme, M. Huttermann, B. Kadenbach and M. Tulinius for patient samples; and A. Tzagoloff for communicating unpublished data. This work was supported by grants from the National Institutes of Health (NS28828, NS32527, NS11766, HL59657 and HD32062), the Muscular Dystrophy Association and a Neil Hamilton Fairley NHMRC Postdoctoral Fellowship (C.M.S.).

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, Aristotle University of Thessaloniki, Thessaloniki, Macedonia, Greece
    Lefkothea C. Papadopoulou
  2. Department of Neurology, New York, New York, USA
    Carolyn M. Sue, Mercy M. Davidson, Kurenai Tanji, Ichizo Nishino, James E. Sadlock, Sindu Krishna, Winsome Walker, Sara Shanske, Darryl C. De Vivo, Eduardo Bonilla, Michio Hirano, Salvatore DiMauro & Eric A. Schon
  3. Department of Pediatrics, New York, New York, USA
    Jeanette Selby
  4. Department of Pathology, New York, New York, USA
    Eduardo Bonilla
  5. Genetics and Development, Columbia University, New York, New York, USA
    Eric A. Schon
  6. Department of Medical Genetics, University of Alberta, Edmonton, Canada
    D. Moira Glerum
  7. Kinderkliniek "C. Hoopt," University Hospital, Ghent, Belgium
    Rudy Van Coster & Gilles Lyon
  8. Clinique St. Vincent, Liege, Belgium
    Emmanuel Scalais
  9. Genetics Services, Inc., Glen Ellyn, Illinois, USA
    Roger Lebel
  10. Division of Metabolism, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
    Paige Kaplan

Authors

  1. Lefkothea C. Papadopoulou
  2. Carolyn M. Sue
  3. Mercy M. Davidson
  4. Kurenai Tanji
  5. Ichizo Nishino
  6. James E. Sadlock
  7. Sindu Krishna
  8. Winsome Walker
  9. Jeanette Selby
  10. D. Moira Glerum
  11. Rudy Van Coster
  12. Gilles Lyon
  13. Emmanuel Scalais
  14. Roger Lebel
  15. Paige Kaplan
  16. Sara Shanske
  17. Darryl C. De Vivo
  18. Eduardo Bonilla
  19. Michio Hirano
  20. Salvatore DiMauro
  21. Eric A. Schon

Corresponding author

Correspondence toEric A. Schon.

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Papadopoulou, L., Sue, C., Davidson, M. et al. Fatal infantile cardioencephalomyopathy with COX deficiency and mutations in SCO2, a COX assembly gene.Nat Genet 23, 333–337 (1999). https://doi.org/10.1038/15513

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