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Multiple mtDNA deletions features in autosomal dominant and recessive diseases suggest distinct pathogeneses
R Carrozzo1, M Hirano, B Fromenty
1Department of Neurology, H. Houston Merritt Clinical Research Center for Muscular Dystrophy and Related Diseases, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Abstract:
Multiple mitochondrial DNA (mtDNA) deletions have been described in patients with autosomal dominant progressive external ophthalmoplegia (AD-PEO) and in autosomal recessive disorders including mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) and autosomal recessive cardiomyopathy ophthalmoplegia (ARCO). The pathogenic bases of these disorders are unknown. We studied three patients with AD-PEO and three patients with autosomal recessive (AR)-PEO (two patients with MNGIE and one patient with ARCO). Histochemistry and Southern blot analyses of DNA were performed in skeletal muscle from the patients. Muscle mtDNA was used to characterize the pattern and amounts of the multiple mtDNA rearrangements; PCR analysis was performed to obtain finer maps of the deleted regions in both conditions. The patients with AD-PEO had myopathic features; the patients with AR-PEO had multisystem disorders. The percentage of ragged-red and cytochrome c oxidase-negative fibers tended to be higher in muscle from the patients with AD-PEO (19% +/- 13.9, 29.7 +/- 26.3) than in muscle from the patients with AR-PEO (1.4% +/- 1.4, 3.3% +/- 3.2; p < 0.10). The sizes of the multiple mtDNA deletions ranged from approximately 4.0 to 10.0 kilobases in muscle from both groups of patients, and in both groups, we identified only deleted and no duplicated mtDNA molecules. Patients with AD-PEO harbored a greater proportion of deleted mtDNA species in muscle (31% +/- 5.3) than did patients with AR-PEO (9.7% +/- 9.1; p < 0.05). In the patients with AD-PEO, we identified a deletion that included the mtDNA heavy strand promoter (HSP) region, which had been previously described as the HSP deletion. The HSP deletion was not present in the patients with AR-PEO. Our findings show the clinical, histologic, and molecular genetic heterogeneity of these complex disorders. In particular, the proportions of multiple mtDNA deletions were higher in muscle samples from patients with AD-PEO than in those from patients with AR-PEO.
Insights
Autosomal dominant progressive external ophthalmoplegia (AD-PEO) patients show higher proportions of multiple mitochondrial DNA (mtDNA) deletions in muscle compared to autosomal recessive (AR)-PEO patients. This suggests distinct molecular mechanisms underlying these PEO subtypes.
Area of Science:
- Mitochondrial Genetics
- Neuromuscular Disorders
- Human Genetics
Background:
- Multiple mitochondrial DNA (mtDNA) deletions are implicated in progressive external ophthalmoplegia (PEO) and other mitochondrial diseases.
- Autosomal dominant (AD-PEO) and autosomal recessive (AR-PEO) forms of PEO, including MNGIE and ARCO, present with varying clinical features.
- The underlying molecular genetic causes for these mtDNA deletion disorders remain largely unknown.
Purpose of the Study:
- To investigate and compare the molecular genetic characteristics of multiple mtDNA deletions in patients with AD-PEO and AR-PEO.
- To correlate clinical and histological findings with mtDNA deletion patterns in affected muscle tissue.
Main Methods:
- Studied three patients with AD-PEO and three with AR-PEO (two MNGIE, one ARCO).
- Performed histochemistry and Southern blot analysis on skeletal muscle DNA to characterize mtDNA rearrangements.
- Utilized PCR analysis for fine mapping of deleted regions within the mtDNA.
Main Results:
- AD-PEO patients exhibited myopathic features, while AR-PEO patients presented with multisystem disorders.
- Higher percentages of ragged-red and COX-negative fibers were observed in AD-PEO muscle compared to AR-PEO muscle.
- Patients with AD-PEO had a significantly greater proportion of deleted mtDNA species (31%) in muscle than AR-PEO patients (9.7%).
- A specific deletion including the mtDNA heavy strand promoter (HSP) region was identified in AD-PEO patients but not in AR-PEO patients.
Conclusions:
- Findings highlight the clinical, histological, and molecular genetic heterogeneity among PEO subtypes.
- The proportion of multiple mtDNA deletions is significantly higher in muscle from AD-PEO patients compared to AR-PEO patients.
- The presence of the HSP deletion may be specific to AD-PEO, suggesting distinct pathogenic mechanisms.