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Threshold expression of the tRNA(Lys) A8344G mutation in single muscle fibres
A R Moslemi1, M Tulinius, E Holme
1Department of Pathology, Sahlgrenska University Hospital, Göteborg, Sweden.
Abstract:
We investigated the distribution in skeletal muscle of mitochondrial DNA (mtDNA) with the tRNA(Lys) A8344G mutation, which is associated with myoclonus epilepsy and ragged red fibres (MERRF) syndrome. Isolated muscle fibre segments (n = 144) from six individuals of two different families carrying the mutation were studied. Two of these individuals were affected by MERRF while four had no or minor clinical symptoms. In one individual with a low overall level of mutated mtDNA (mean 18%) the variation in the proportion of mutated mtDNA between individual muscle fibres ranged from 0 to 80%. This result demonstrates that segregation of the tRNA(Lys) A8344G mutation within a tissue may lead to very marked variation of the level of mutated mtDNA between individual cells. There was a very high apparent threshold level of mutated mtDNA (95.3-97.7%) for expression of histochemical cytochrome c oxidase (COX) deficiency in individual muscle fibres. The results indicated that this apparent threshold level varied slightly between patients. Ultrastructural examination revealed that an appreciable proportion of the mitochondria in COX-positive muscle fibres lacked COX activity. Variation in intercellular and interorganellar distribution of mutated mtDNA in addition to the absolute mtDNA copy number may explain differences in clinical phenotypes in patients with high levels of the tRNA(Lys) A8344G mutation.
Insights
Mitochondrial DNA (mtDNA) mutations causing myoclonus epilepsy and ragged red fibres (MERRF) syndrome show significant variation between muscle cells. This cellular distribution impacts disease presentation and cytochrome c oxidase deficiency thresholds.
Area of Science:
- Genetics
- Cell Biology
- Neurology
Background:
- Investigating the pathogenic mitochondrial DNA (mtDNA) tRNA(Lys) A8344G mutation linked to myoclonus epilepsy and ragged red fibres (MERRF) syndrome.
- Studying the distribution of this mutation within skeletal muscle tissue.
Observation:
- Examined 144 muscle fibre segments from six individuals with the mutation, two affected by MERRF and four asymptomatic.
- Observed extreme variation in mutated mtDNA levels (0-80%) between individual muscle fibres in one individual.
- Identified a high threshold (95.3-97.7%) of mutated mtDNA for cytochrome c oxidase (COX) deficiency in muscle fibres, with slight patient-to-patient variation.
Findings:
- Demonstrated significant segregation of the tRNA(Lys) A8344G mutation within skeletal muscle, leading to substantial intercellular variation in mutated mtDNA levels.
- Found that even COX-positive muscle fibres contained mitochondria lacking COX activity.
- Indicated that intercellular and interorganellar distribution of mutated mtDNA, along with mtDNA copy number, influences clinical phenotypes in MERRF patients.
Implications:
- Highlights the importance of cellular mtDNA distribution in understanding MERRF syndrome pathogenesis.
- Suggests that variability in mutation load between cells is a key factor in disease expression.
- Provides insights into the complex relationship between genotype, mtDNA heteroplasmy, and clinical outcomes in mitochondrial disorders.