title: Aberrant synthesis of ATP synthase resulting from a novel deletion in mitochondrial DNA in an African patient with progressive external ophthalmoplegia.
abstract: A young, adult, African male patient presented with progressive proximal muscle weakness, external ophthalmoplegia and ptosis, as well as cardiac conduction abnormalities resembling Kearns-Sayre syndrome (KSS). Magnetic resonance imaging (MRI) of the brain revealed normal basal ganglia but bilateral well-circumscribed lesions in the cerebellar peduncles. Enzyme deficiencies in oxidative phosphorylation (OXPHOS) complexes I, IV and V was measured in muscle tissue. Blue native polyacrylamide gel electrophoresis (BN-PAGE) confirmed decreased protein content and activity of these complexes and revealed the presence of two catalytically active complex V sub-complexes. Upon investigation by molecular genetics, the mitochondrial DNA (mtDNA) copy number was found to be elevated and a novel deletion of 3431 bp was found in 80% of muscle mtDNA between positions 7115 and 10546, flanked by a 5 bp direct repeat sequence. In addition, it could also be concluded that the absence of mtDNA-encoded ATPase6 and ATPase8 genes in this patient clearly resulted in aberrant synthesis of ATP synthase.
authors.affiliation: Centre for Human Metabonomics, North-West University, Potchefstroom, South Africa.
authors.forename: Francois H
authors.initials: FH
authors.lastname: van der Westhuizen
authors.forename: Joél
authors.initials: J
authors.lastname: Smet
authors.forename: Oksana
authors.initials: O
authors.lastname: Levanets
authors.forename: Madelein
authors.initials: M
authors.lastname: Meissner-Roloff
authors.forename: Roan
authors.initials: R
authors.lastname: Louw
authors.forename: Rudy
authors.initials: R
authors.lastname: Van Coster
authors.forename: Izelle
authors.initials: I
authors.lastname: Smuts
mesh_terms: D001741:Black or African American / Q000235:genetics*; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics*; D045222:Electron Transport Chain Complex Proteins / Q000235:genetics; D004591:Electrophoresis, Polyacrylamide Gel; D004734:Energy Metabolism / Q000235:genetics; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D025261:Mitochondrial Proton-Translocating ATPases / Q000235:genetics*; D017246:Ophthalmoplegia, Chronic Progressive External / Q000175:diagnosis / Q000201:enzymology / Q000208:ethnology / Q000235:genetics*; D010085:Oxidative Phosphorylation; D010641:Phenotype; D017384:Sequence Deletion; D055815:Young Adult
chemical_list: D004272:DNA, Mitochondrial; D045222:Electron Transport Chain Complex Proteins; C501005:MT-ATP6 protein, human; C513300:MT-ATP8 protein, human; D025261:Mitochondrial Proton-Translocating ATPases