Aberrant synthesis of ATP synthase resulting from a novel deletion in mitochondrial DNA in an African patient with progressive external ophthalmoplegia

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