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Directly repeated sequences associated with pathogenic mitochondrial DNA deletions.
D R Johns1, S L Rutledge, O C Stine
1Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
Summary
Large mitochondrial DNA deletions causing chronic progressive external ophthalmoplegia often arise from recombinational events. These deletions occur at specific repeated sequences within the mitochondrial genome, suggesting a common mechanism.
Area of Science:
- Genetics
- Molecular Biology
- Neurology
Background:
- Chronic progressive external ophthalmoplegia (CPEO) is a debilitating neuromuscular disorder.
- Large deletions of mitochondrial DNA (mtDNA) are a known cause of CPEO.
- The precise molecular mechanisms leading to these mtDNA deletions are not fully understood.
Purpose of the Study:
- To determine the nucleotide sequences at the breakpoints of large mtDNA deletions in CPEO patients.
- To investigate the potential role of sequence homology and recombination in the formation of these deletions.
Main Methods:
- Nucleotide sequencing of junctional regions of deleted mtDNA.
- Comparative analysis of deletion breakpoints and flanking sequences.
- Identification of repeated sequences and consensus sequences within the mitochondrial genome.
Main Results:
- Deletion breakpoints in four unrelated CPEO patients consistently occurred within 13-18 base pair direct repeat sequences.
- These direct repeats were located in different regions of the normal mitochondrial genome, separated by 4.5-7.7 kilobases.
- A consensus sequence of 11 nucleotides emerged from comparing the repeat sequences, resembling recombination signals.
- Identical deletions were observed in two patients, and both normal and deleted mtDNA were present in varying proportions across tissues.
Conclusions:
- The findings strongly suggest that large mtDNA deletions in CPEO result from a recombinational event mediated by direct repeats.
- The presence of both normal and deleted mtDNA in various tissues indicates that these mutations likely occurred early in development, before primary germ layer differentiation.