Mitochondrial Encephalomyopathy and Complex III Deficiency Associated with a Stop-Codon Mutation in the Cytochrome b Gene
| Autor: | Nancy G. Kennaway, J. Andrew Keightley, Neil R. M. Buist, Roberto Anitori, Franklin Quan, Miriam D. Burton |
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| Rok vydání: | 2000 |
| Předmět: |
Mitochondrial encephalomyopathy
Adult Male Cytochrome Adolescent Immunocytochemistry Mutant DNA Mutational Analysis Molecular Sequence Data Muscle Fibers Skeletal Biology DNA Mitochondrial Polymerase Chain Reaction Electron Transport Complex III Mitochondrial Encephalomyopathies medicine Genetics Humans Genetics(clinical) Amino Acid Sequence Cloning Molecular Myopathy Child Muscle Skeletal Genetics (clinical) Base Sequence Cytochrome b Infant Newborn Articles Fibroblasts Middle Aged medicine.disease Cytochrome b Group Molecular biology Immunohistochemistry Coenzyme Q – cytochrome c reductase Mutation biology.protein Rieske protein Codon Terminator Female medicine.symptom Polymorphism Restriction Fragment Length |
| Zdroj: | The American Journal of Human Genetics. 67(6):1400-1410 |
| ISSN: | 0002-9297 |
| DOI: | 10.1086/316900 |
| Popis: | We have reinvestigated a young woman, originally reported by us in 1983, who presented with exercise intolerance and lactic acidosis associated with severe deficiency of complex III and who responded to therapy with menadione and ascorbate. Gradually, she developed symptoms of a mitochondrial encephalomyopathy. Immunocytochemistry of serial sections of muscle showed a mosaic of fibers that reacted poorly with antibodies to subunits of complex III but reacted normally with antibodies to subunits of complexes I, II, or IV, suggesting a mutation of mtDNA. These findings demonstrate the diagnostic value of immunocytochemistry in identifying specific respiratory-chain deficiencies and, potentially, distinguishing between nuclear- or mtDNA-encoded defects. Sequence analysis revealed a stop-codon mutation (G15242A) in the mtDNA-encoded cytochrome b gene, resulting in loss of the last 215 amino acids of cytochrome b. PCR-RFLP analysis indicated that the G15242A mutation was heteroplasmic and was present in a high percentage (87%) of affected tissue (skeletal muscle) and a low percentage (0.7%) of unaffected tissue (blood) but was not detected in controls. Analysis of microdissected muscle fibers showed a significant correlation between the immunoreactivity toward the Rieske protein of complex III and the percentage of mutant mtDNA: immunopositive fibers had a median value of 33% of the G15242A mutation, whereas immunonegative, ragged-red fibers had a median value of 89%, indicating that the stop-codon mutation was pathogenic in this patient. The G15242A mutation was also present in several other tissues, including hair roots, indicating that it must have arisen either very early in embryogenesis, before separation of the primary germ layers, or in the maternal germ line. The findings in this patient are contrasted with other recently described patients who have mutations in the cytochrome b gene. |
| Databáze: | OpenAIRE |
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