Phenotype-genotype correlations in skeletal muscle of patients with mtDNA deletions.

Large-scale deletions of mitochondrial DNA (mtDNA) have been associated with a subgroup of mitochondrial encephalomyopathies, usually characterized by progressive external ophthalmoplegia (PEO) and mitochondrial proliferation in muscle fibers. We and others have shown that muscle from patients with mtDNA deletions have variable cytochrome c oxidase (COX) deficiency and reduction of mitochondrially-synthesized polypeptides in affected muscle fibers. The present work summarizes the phenotype-genotype correlations observed in patients' muscle. In situ hybridization revealed that, while most COX-deficient fibers had increased levels of mutant mtDNA, they almost invariably had reduced levels of normal mtDNA. PCR quantitation of both deleted and wild-type mtDNAs in normal and respiration-deficient muscle fibers from patients with the "common deletion" showed that deleted mtDNAs were present in normal fibers (31 +/- 26%), but their percentages were much higher in affected fibers (95% +/- 2%). Absolute levels of deleted mtDNA were also increased in affected fibers, whereas absolute levels of wild-type mtDNA were significantly reduced. Taken together, our results suggest that although a specific ratio between mutant and wild-type mitochondrial genomes is probably the major determinant of the respiratory chain deficiency associated with mtDNA deletions, the reduction in the absolute amounts of wild-type mtDNA may also play a significant pathogenetic role.