title: Recurrent myoglobinuria due to a nonsense mutation in the COX I gene of mitochondrial DNA.
abstract: OBJECTIVE
  To elucidate the molecular basis of a mitochondrial myopathy associated with recurrent myoglobinuria and cytochrome c oxidase (COX) deficiency in muscle.
  
  
  BACKGROUND
  Recurrent myoglobinuria is typically seen in patients with inborn errors of carbohydrate or lipid metabolism, the main sources of energy for muscle contraction. Relatively little attention has been directed to defects of the mitochondrial respiratory chain in patients with otherwise unexplained recurrent myoglobinuria.
  
  
  METHODS
  Having documented COX deficiency histochemically and biochemically in the muscle biopsy from a patient with exercise-induced recurrent myoglobinuria, the authors sequenced the three mitochondrial DNA (mtDNA)-encoded COX genes, and performed restriction fragment length polymorphism analysis and single-fiber PCR.
  
  
  RESULTS
  The authors identified a nonsense mutation (G5920A) in the COX I gene in muscle mtDNA. The mutation was heteroplasmic and abundantly present in COX-negative fibers, but less abundant or absent in COX-positive fibers; it was not found in blood or fibroblasts from the patient or in blood samples from the patient's asymptomatic mother and sister.
  
  
  CONCLUSIONS
  The G5920A mutation caused COX deficiency in muscle, explaining the exercise intolerance and the low muscle capacity for oxidative phosphorylation documented by cycle ergometry. The sporadic occurrence of this mutation in muscle alone suggests that it arose de novo in myogenic stem cells after germ-layer differentiation. Mutations in mtDNA-encoded COX genes should be considered in patients with recurrent myoglobinuria.
authors.affiliation: Department of Neurology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Karadimas
authors.forename: P
authors.initials: P
authors.lastname: Greenstein
authors.forename: C M
authors.initials: CM
authors.lastname: Sue
authors.forename: J T
authors.initials: JT
authors.lastname: Joseph
authors.forename: K
authors.initials: K
authors.lastname: Tanji
authors.forename: R G
authors.initials: RG
authors.lastname: Haller
authors.forename: T
authors.initials: T
authors.lastname: Taivassalo
authors.forename: M M
authors.initials: MM
authors.lastname: Davidson
authors.forename: S
authors.initials: S
authors.lastname: Shanske
authors.forename: E
authors.initials: E
authors.lastname: Bonilla
authors.forename: S
authors.initials: S
authors.lastname: DiMauro
mesh_terms: D000328:Adult; D004272:DNA, Mitochondrial / Q000235:genetics*; D003576:Electron Transport Complex IV / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D009132:Muscles / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D009212:Myoglobinuria / Q000209:etiology* / Q000235:genetics* / Q000503:physiopathology; D012150:Polymorphism, Restriction Fragment Length; D012008:Recurrence
chemical_list: D004272:DNA, Mitochondrial; D003576:Electron Transport Complex IV