A mutation in C2orf64 causes impaired cytochrome c oxidase assembly and mitochondrial cardiomyopathy

Am J Hum Genet. 2011 Apr 8;88(4):488-93. doi: 10.1016/j.ajhg.2011.03.002. Epub 2011 Mar 31.


The assembly of mitochondrial respiratory chain complex IV (cytochrome c oxidase) involves the coordinated action of several assembly chaperones. In Saccharomyces cerevisiae, at least 30 different assembly chaperones have been identified. To date, pathogenic mutations leading to a mitochondrial disorder have been identified in only seven of the corresponding human genes. One of the genes for which the relevance to human pathology is unknown is C2orf64, an ortholog of the S. cerevisiae gene PET191. This gene has previously been shown to be a complex IV assembly factor in yeast, although its exact role is still unknown. Previous research in a large cohort of complex IV deficient patients did not support an etiological role of C2orf64 in complex IV deficiency. In this report, a homozygous mutation in C2orf64 is described in two siblings affected by fatal neonatal cardiomyopathy. Pathogenicity of the mutation is supported by the results of a complementation experiment, showing that complex IV activity can be fully restored by retroviral transduction of wild-type C2orf64 in patient-derived fibroblasts. Detailed analysis of complex IV assembly intermediates in patient fibroblasts by 2D-BN PAGE revealed the accumulation of a small assembly intermediate containing subunit COX1 but not the COX2, COX4, or COX5b subunits, indicating that C2orf64 is involved in an early step of the complex IV assembly process. The results of this study demonstrate that C2orf64 is essential for human complex IV assembly and that C2orf64 mutational analysis should be considered for complex IV deficient patients, in particular those with hypertrophic cardiomyopathy.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Amino Acid Substitution
  • Base Sequence
  • Cardiomyopathies / enzymology*
  • Cardiomyopathies / genetics*
  • Consanguinity
  • DNA Mutational Analysis
  • Electron Transport Complex IV / chemistry*
  • Electron Transport Complex IV / metabolism*
  • Electrophoresis, Gel, Two-Dimensional
  • Fatal Outcome
  • Female
  • Fibroblasts / enzymology
  • Genetic Complementation Test
  • Homozygote
  • Humans
  • Infant, Newborn
  • Male
  • Mitochondrial Diseases / enzymology*
  • Mitochondrial Diseases / genetics*
  • Molecular Sequence Data
  • Mutation, Missense*
  • Open Reading Frames
  • Pedigree
  • Protein Multimerization
  • Sequence Homology, Amino Acid


  • Electron Transport Complex IV