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Metabolic consequences of a novel missense mutation of the mtDNA CO I gene
- Source :
- Scopus-Elsevier
- Publication Year :
- 2002
-
Abstract
- We have identified a novel heteroplasmic C6489A missense mutation in the mitochondrial DNA (mtDNA) CO I gene encoding the cytochrome c oxidase (COX) subunit I in a 17-year-old girl with epilepsia partialis continua. This point mutation leads to an exchange of the highly conserved Leu196 to Ileu196. Muscle biopsy showed in single fibers decreased COX activity and lowered binding of COX antibodies, indicating decreased stability of the mutated enzyme. The analysis of blood mtDNA revealed about 30% mutant mtDNA in the patients blood but about 90% mutant mtDNA in the blood of two non-affected family members. Quantitative analysis of the mutation gene dose effect on COX activity on single muscle fiber level revealed a very high threshold-a COX deficiency was observed only in fibers containing95% mutant mtDNA. In apparent contrast to this high mutation gene dose threshold, in vivo investigations of mitochondrial function in saponin-permeabilized muscle fibers of the index patient containing approximately 90% mutated mtDNA showed decreased maximal rates of respiration and an increased sensitivity of fiber respiration to cyanide. This is due to a 2-fold increase of COX flux control on muscle fiber respiration and a 30% decrease of COX metabolic threshold, supporting the concept of tight COX control of oxidative phosphorylation in skeletal muscle.
- Subjects :
- Mitochondrial DNA
Adolescent
Mutant
DNA Mutational Analysis
Molecular Sequence Data
Drug Resistance
Mutation, Missense
Cytochrome-c Oxidase Deficiency
Epilepsy, Partial, Motor
Mitochondrion
Gene mutation
DNA, Mitochondrial
Oxidative Phosphorylation
Electron Transport Complex IV
Enzyme Stability
Genetics
medicine
Cytochrome c oxidase
Missense mutation
Animals
Humans
Amino Acid Sequence
Muscle, Skeletal
Molecular Biology
Genetics (clinical)
Conserved Sequence
biology
Base Sequence
Sequence Homology, Amino Acid
Point mutation
Skeletal muscle
General Medicine
DNA
Molecular biology
Mitochondria, Muscle
medicine.anatomical_structure
Biochemistry
biology.protein
Female
Subjects
Details
- ISSN :
- 09646906
- Volume :
- 11
- Issue :
- 16
- Database :
- OpenAIRE
- Journal :
- Human molecular genetics
- Accession number :
- edsair.doi.dedup.....4fd3c792bbf362766c38b9cea0a58f35