A missense mutation of cytochrome oxidase subunit II causes defective assembly and myopathy.

Abstract

We report the first missense mutation in the mtDNA gene for subunit II of cytochrome c oxidase (COX). The mutation was identified in a 14-year-old boy with a proximal myopathy and lactic acidosis. Muscle histochemistry and mitochondrial respiratory-chain enzymology demonstrated a marked reduction in COX activity. Immunohistochemistry and immunoblot analyses with COX subunit-specific monoclonal antibodies showed a pattern suggestive of a primary mtDNA defect, most likely involving CO II, for COX subunit II (COX II). mtDNA-sequence analysis demonstrated a novel heteroplasmic T-->A transversion at nucleotide position 7,671 in CO II. This mutation changes a methionine to a lysine residue in the middle of the first N-terminal membrane-spanning region of COX II. The immunoblot studies demonstrated a severe reduction in cross-reactivity, not only for COX II but also for the mtDNA-encoded subunit COX III and for nuclear-encoded subunits Vb, VIa, VIb, and VIc. Steady-state levels of the mtDNA-encoded subunit COX I showed a mild reduction, but spectrophotometric analysis revealed a dramatic decrease in COX I-associated heme a3 levels. These observations suggest that, in the COX protein, a structural association of COX II with COX I is necessary to stabilize the binding of heme a3 to COX I.

• Authors: S Rahman, J W Taanman, J M Cooper, I Nelson, I Hargreaves, B Meunier, M G Hanna, J J García, R A Capaldi, B D Lake, J V Leonard, A H Schapira
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 65 Issue 4 Pg. 1030-9 (Oct 1999) ISSN: 0002-9297 [Print] United States
• PMID: 10486321 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA, Mitochondrial
• Holoenzymes
• heme a
• Heme
• cytochrome C oxidase subunit II
• Electron Transport Complex IV

Topics

• Acidosis, Lactic (enzymology, genetics, metabolism, pathology)
• Adolescent
• Amino Acid Sequence
• Amino Acid Substitution (genetics)
• Base Sequence
• Blotting, Western
• Cell Nucleus (enzymology)
• Cell Respiration
• Cells, Cultured
• Cytochrome-c Oxidase Deficiency
• DNA, Mitochondrial (genetics)
• Electron Transport Complex IV (chemistry, genetics, metabolism)
• Enzyme Stability
• Heme (analogs & derivatives, metabolism)
• Holoenzymes (chemistry, deficiency, genetics, metabolism)
• Humans
• Immunohistochemistry
• Male
• Mitochondria (enzymology, genetics, metabolism, pathology)
• Models, Molecular
• Molecular Sequence Data
• Muscles (enzymology, metabolism, pathology)
• Muscular Diseases (enzymology, genetics, metabolism, pathology)
• Mutation, Missense (genetics)
• Photolysis
• Polarography
• Protein Structure, Quaternary
• Sequence Alignment