title: Association of myopathy with large-scale mitochondrial DNA duplications and deletions: which is pathogenic?
abstract: We identified large-scale heteroplasmic mitochondrial DNA (mtDNA) rearrangements in a 50-year-old woman with an adult-onset progressive myopathy. The predominant mtDNA abnormality was a 21.2-kb duplicated molecule. In addition, a small population of the corresponding partially deleted 4.6-kb molecule was detected. Skeletal muscle histology revealed fibers that were negative for cytochrome c oxidase (COX) activity and had reduced mtDNA-encoded COX subunits. By single-fiber polymerase chain reaction analysis, COX-negative fibers contained a low number of wild-type or duplicated mtDNA molecules (ie, nondeleted). In situ hybridization demonstrated that the abnormal fibers contained increased amounts of mtDNA compared with normal fibers and that most of the genomes were deleted. We concluded that deleted mtDNA molecules were primarily responsible for the phenotype in this patient.
authors.affiliation: H. Houston Merritt Clinical Research Center for Muscular Dystrophy and Related Disorders, and Department of Neurology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: G
authors.initials: G
authors.lastname: Manfredi
authors.forename: T
authors.initials: T
authors.lastname: Vu
authors.forename: E
authors.initials: E
authors.lastname: Bonilla
authors.forename: E A
authors.initials: EA
authors.lastname: Schon
authors.forename: S
authors.initials: S
authors.lastname: DiMauro
authors.forename: E
authors.initials: E
authors.lastname: Arnaudo
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.forename: L P
authors.initials: LP
authors.lastname: Rowland
authors.forename: M
authors.initials: M
authors.lastname: Hirano
mesh_terms: D001483:Base Sequence; D030401:Cytochrome-c Oxidase Deficiency; D004272:DNA, Mitochondrial / Q000235:genetics*; D003576:Electron Transport Complex IV / Q000235:genetics*; D005260:Female; D015321:Gene Rearrangement; D006801:Humans; D017403:In Situ Hybridization; D008875:Middle Aged; D017240:Mitochondrial Myopathies / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D018485:Muscle Fibers, Skeletal / Q000201:enzymology / Q000473:pathology; D018482:Muscle, Skeletal / Q000201:enzymology / Q000473:pathology; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D012091:Repetitive Sequences, Nucleic Acid; D017384:Sequence Deletion
chemical_list: D004272:DNA, Mitochondrial; D003576:Electron Transport Complex IV