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Phenotype–genotype correlations in skeletal muscle of patients with mtDNA deletions
Author(s) -
Moraes C. T.,
Sciacco M.,
Ricci E.,
Tengan C. H.,
Hao H.,
Bonilla E.,
Schon E. A.,
DiMauro S.
Publication year - 1995
Publication title -
muscle and nerve
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.025
H-Index - 145
eISSN - 1097-4598
pISSN - 0148-639X
DOI - 10.1002/mus.880181429
Subject(s) - mitochondrial dna , mitochondrial encephalomyopathies , biology , chronic progressive external ophthalmoplegia , cytochrome c oxidase , microbiology and biotechnology , genotype , mitochondrial myopathy , mitochondrion , respiratory chain , phenotype , genetics , mutant , skeletal muscle , gene , endocrinology
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‐dificient 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. © 1995 John Wiley & Sons, Inc.