PHENOTYPE GENOTYPE CORRELATIONS IN SKELETAL-MUSCLE OF PATIENTS WITH MTDNA DELETIONS

Large-scale deletions of mitochondrial DNA (mtDNA) have been associate d with a subgroup of mitochondrial encephalomyopathies, usually charac terized by progressive external ophthalmoplegia (PEO) and mitochondria l 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 polypep tides in affected muscle fibers, The present work summarizes the pheno type-genotype correlations observed in patients' muscle, In situ hybri dization revealed that, while most COX-deficient fibers had increased levels of mutant mtDNA, they almost invariably had reduced levels of n ormal 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 affecte d fibers (95% +/- 2%), Absolute levels of deleted mtDNA were also incr eased in affected fibers, whereas absolute levels of wild-type mtDNA w ere significantly reduced, Taken together, our results suggest that al though a specific ratio between mutant and wild-type mitochondrial gen omes is probably the major determinant of the respiratory chain defici ency associated with mtDNA deletions, the reduction in the absolute am ounts of wild-type mtDNA may also play a significant pathogenetic role . (C) 1995 John Wiley and Sons, Inc.