In an African American patient with isolated ophthalmoplegia, Moraes et al. (1993) identified a G-to-A transition at position 5703 of the mitochondrial DNA, located in the anticodon stem of the tRNA-asn gene. The mutation disrupted the first basepair of the anticodon stem, a secondary structure highly conserved throughout evolution. This transition also disrupted a DdeI restriction endonuclease site, allowing for easy detection of the mutation by RFLP analysis of PCR fragments. RFLP analysis of DdeI recognition sites had been used extensively in establishing the origins of human populations. From a total of 818 individuals examined, 64 of whom were of African ancestry, there were no reports of a DdeI polymorphic site at position 5703. In addition, none of 57 patients with mitochondrial disease possessed this alteration. In addition to this disease-producing mutation, the proposita had a large number of polymorphisms consistent with her African ancestry. Most of these were located in evolutionarily nonconserved regions and were considered neutral polymorphisms.
Hao and Moraes (1997) found that expression of the MTTN 5703G-A mutation in human osteosarcoma cells resulted in severe impairment of oxidative phosphorylation and mitochondrial protein synthesis. Gel electrophoresis showed that the mutant tRNA fraction had an altered conformation consistent with a destabilized secondary or tertiary structure, which may result in impaired aminoacylation or increased in vivo tRNA degradation by mitochondrial RNases.
Vives-Bauza et al. (2003) reported a girl with the MTTN 5703G-A mutation and isolated progressive ophthalmoplegia beginning at age 4 years. There was no involvement of other cranial nerves nor signs of cardiac, hepatic, or CNS involvement. Physical examination at age 16 years showed moderate progression of ptosis and ophthalmoplegia as well as marked loss of subcutaneous fat and increasing muscle fatigue. Vives-Bauza et al. (2003) noted the phenotypic similarity to the patient reported by Moraes et al. (1993).
