Human Molecular Genetics Advance Access originally published online on August 19, 2003
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Human Molecular Genetics, 2003, Vol. 12, No. 20 2693-2702
DOI: 10.1093/hmg/ddg284
© 2003 Oxford University Press
Mutations in COX10 result in a defect in mitochondrial heme A biosynthesis and account for multiple, early-onset clinical phenotypes associated with isolated COX deficiency
1Montreal Neurological Institute and 2Department of Human Genetics, McGill University, Montreal H3A 2B4, Canada, 3Department of Pediatrics and 4Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, OR 97201, USA and 5Metabolic Disease Centre Munich-Schwabing and Institute of Clinical Chemistry, Molecular Diagnostics and Mitochondrial Genetics, 80804 Munich, Germany
Received June 20, 2003; Accepted August 1, 2003
Deficiencies in the activity of cytochrome c oxidase (COX) are an important cause of autosomal recessive respiratory chain disorders. Patients with isolated COX deficiency are clinically and genetically heterogeneous, and mutations in several different assembly factors have been found to cause specific clinical phenotypes. Two of the most common clinical presentations, Leigh Syndrome and hypertrophic cardiomyopathy, have so far only been associated with mutations in SURF1 or SCO2 and COX15, respectively. Here we show that expression of COX10 from a retroviral vector complements the COX deficiency in a patient with anemia and Leigh Syndrome, and in a patient with anemia, sensorineural deafness and fatal infantile hypertrophic cardiomyopathy. A partial rescue was also obtained following microcell-mediated transfer of mouse chromosomes into patient fibroblasts. COX10 functions in the first step of the mitochondrial heme A biosynthetic pathway, catalyzing the conversion of protoheme (heme B) to heme O via the farnesylation of a vinyl group at position C2. Heme A content was reduced in mitochondria from patient muscle and fibroblasts in proportion to the reduction in COX enzyme activity and the amount of fully assembled enzyme. Mutation analysis of COX10 identified four different missense alleles, predicting amino acid substitutions at evolutionarily conserved residues. A topological model places these residues in regions of the protein shown to have important catalytic functions by mutation analysis of a prokaryotic ortholog. Mutations in COX10 have previously been reported in a single family with tubulopathy and leukodystrophy. This study shows that mutations in this gene can cause nearly the full range of clinical phenotypes associated with early onset isolated COX deficiency.
* To whom correspondence should be addressed at: Montreal Neurological Institute, 3801 University Street, Montreal, Quebec, Canada H3A 2B4. Tel: +1 5143988523; Fax: +1 5143981509; Email: eric{at}ericpc.mni.mcgill.ca
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  D. C. Wallace and W. Fan The pathophysiology of mitochondrial disease as modeled in the mouse Genes & Dev., August 1, 2009; 23(15): 1714 - 1736. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Mogi Probing Structure of Heme A Synthase from Bacillus subtilis by Site-Directed Mutagenesis J. Biochem., May 1, 2009; 145(5): 625 - 633. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Mogi Over-Expression and Characterization of Bacillus subtilis Heme O Synthase J. Biochem., May 1, 2009; 145(5): 669 - 675. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. Suthammarak, Y.-Y. Yang, P. G. Morgan, and M. M. Sedensky Complex I Function Is Defective in Complex IV-deficient Caenorhabditis elegans J. Biol. Chem., March 6, 2009; 284(10): 6425 - 6435. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Zhu, X. Peng, M.-X. Guan, and Q. Yan Pathogenic mutations of nuclear genes associated with mitochondrial disorders Acta Biochim Biophys Sin, March 1, 2009; 41(3): 179 - 187. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z. Wang, Y. Wang, and E. L. Hegg Regulation of the Heme A Biosynthetic Pathway: DIFFERENTIAL REGULATION OF HEME A SYNTHASE AND HEME O SYNTHASE IN SACCHAROMYCES CEREVISIAE J. Biol. Chem., January 9, 2009; 284(2): 839 - 847. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. J. Staley, K. B. Sims, P. E. Grant, and E. T. Hedley-Whyte Case 28-2008 -- An 8-Day-Old Infant with Congenital Deafness, Lethargy, and Hypothermia N. Engl. J. Med., September 11, 2008; 359(11): 1156 - 1167. [Full Text] [PDF]
|
|
|
|
 |
|
 F. Pierrel, O. Khalimonchuk, P. A. Cobine, M. Bestwick, and D. R. Winge Coa2 Is an Assembly Factor for Yeast Cytochrome c Oxidase Biogenesis That Facilitates the Maturation of Cox1 Mol. Cell. Biol., August 15, 2008; 28(16): 4927 - 4939. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Son, S. C. Leary, N. Romain, F. Pierrel, D. R. Winge, R. G. Haller, and J. L. Elliott Isolated Cytochrome c Oxidase Deficiency in G93A SOD1 Mice Overexpressing CCS Protein J. Biol. Chem., May 2, 2008; 283(18): 12267 - 12275. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Diaz, H. Fukui, S. Garcia, and C. T. Moraes Cytochrome C oxidase is required for the assembly/stability of respiratory complex I in mouse fibroblasts. Mol. Cell. Biol., July 1, 2006; 26(13): 4872 - 4881. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J.H. Coenen, J. A.M. Smeitink, J. M. Pots, E. van Kaauwen, F. J.M. Trijbels, F. A. Hol, and L. P. van den Heuvel Sequence Analysis of the Structural Nuclear Encoded Subunits and Assembly Genes of Cytochrome c Oxidase in a Cohort of 10 Isolated Complex IV--Deficient Patients Revealed Five Mutations J Child Neurol, June 1, 2006; 21(6): 508 - 511. [Abstract] [PDF]
|
|
|
|
 |
|
 F. Diaz, C. K. Thomas, S. Garcia, D. Hernandez, and C. T. Moraes Mice lacking COX10 in skeletal muscle recapitulate the phenotype of progressive mitochondrial myopathies associated with cytochrome c oxidase deficiency Hum. Mol. Genet., September 15, 2005; 14(18): 2737 - 2748. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. K. H. Tay, C. Nesti, M. Mancuso, E. A. Schon, S. Shanske, E. Bonilla, M. M. Davidson, and S. DiMauro Studies of COX16, COX19, and PET191 in Human Cytochrome-c Oxidase Deficiency Arch Neurol, December 1, 2004; 61(12): 1935 - 1937. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. C. Leary, B. A. Kaufman, G. Pellecchia, G.-H. Guercin, A. Mattman, M. Jaksch, and E. A. Shoubridge Human SCO1 and SCO2 have independent, cooperative functions in copper delivery to cytochrome c oxidase Hum. Mol. Genet., September 1, 2004; 13(17): 1839 - 1848. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C E Oquendo, H Antonicka, E A Shoubridge, W Reardon, and G K Brown Functional and genetic studies demonstrate that mutation in the COX15 gene can cause Leigh syndrome J. Med. Genet., July 1, 2004; 41(7): 540 - 544. [Full Text] [PDF]
|
|
|
|
|
|
S. L. Williams, I. Valnot, P. Rustin, and J.-W. Taanman Cytochrome c Oxidase Subassemblies in Fibroblast Cultures from Patients Carrying Mutations in COX10, SCO1, or SURF1 J. Biol. Chem., February 27, 2004; 279(9): 7462 - 7469. [Abstract] [Full Text] [PDF]
|
|