A novel mitochondrial ATP8 gene mutation in a patient with apical hypertrophic cardiomyopathy and neuropathy

J Med Genet. 2008 Mar;45(3):129-33. doi: 10.1136/jmg.2007.052084. Epub 2007 Oct 22.


Purpose: To identify the biochemical and molecular genetic defect in a 16-year-old patient presenting with apical hypertrophic cardiomyopathy and neuropathy suspected for a mitochondrial disorder.

Methods: Measurement of the mitochondrial energy-generating system (MEGS) capacity in muscle and enzyme analysis in muscle and fibroblasts were performed. Relevant parts of the mitochondrial DNA were analysed by sequencing. Transmitochondrial cybrids were obtained by fusion of 143B206 TK(-) rho zero cells with patient-derived enucleated fibroblasts. Immunoblotting techniques were applied to study the complex V assembly.

Results: A homoplasmic nonsense mutation m.8529G-->A (p.Trp55X) was found in the mitochondrial ATP8 gene in the patient's fibroblasts and muscle tissue. Reduced complex V activity was measured in the patient's fibroblasts and muscle tissue, and was confirmed in cybrid clones containing patient-derived mitochondrial DNA. Immunoblotting after blue native polyacrylamide gel electrophoresis showed a lack of holocomplex V and increased amounts of mitochondrial ATP synthase subcomplexes. An in-gel activity assay of ATP hydrolysis showed activity of free F(1)-ATPase in the patient's muscle tissue and in the cybrid clones.

Conclusion: We describe the first pathogenic mutation in the mitochondrial ATP8 gene, resulting in an improper assembly and reduced activity of the complex V holoenzyme.

Publication types

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

MeSH terms

  • Adolescent
  • Amino Acid Sequence
  • Base Sequence
  • Cardiomyopathy, Hypertrophic / enzymology*
  • Cardiomyopathy, Hypertrophic / genetics*
  • Codon, Nonsense*
  • DNA Primers / genetics
  • Genes, Mitochondrial*
  • Humans
  • Hybrid Cells
  • Male
  • Mitochondrial Diseases / enzymology
  • Mitochondrial Diseases / genetics
  • Mitochondrial Proton-Translocating ATPases / chemistry
  • Mitochondrial Proton-Translocating ATPases / deficiency*
  • Mitochondrial Proton-Translocating ATPases / genetics*
  • Molecular Sequence Data
  • Nervous System Diseases / enzymology*
  • Nervous System Diseases / genetics*
  • Sequence Homology, Amino Acid


  • Codon, Nonsense
  • DNA Primers
  • complex V (mitochondrial oxidative phosphorylation system)
  • Mitochondrial Proton-Translocating ATPases