A novel mitochondrial 12SrRNA point mutation in parkinsonism, deafness, and neuropathy.

The objective of this study was to determine whether a mitochondrial DNA mutation and defective oxidative phosphorylation are present in a pedigree with maternally inherited sensorineural deafness, levodopa-responsive parkinsonism, and neuropathy. We sequenced the mitochondrial-encoded ribosomal RNA, cytochrome c oxidase, and transfer RNA genes by cycle sequencing. A polymerase chain reaction–based restriction enzyme assay with mismatched primers was employed to show heteroplasmy of a novel 12SrRNA mutation in the proband and to screen control subjects. Spectrophotometric mitochondrial respiratory chain assays were performed in transformed lymphoblasts from the proband and 12 normal controls. A novel, heteroplasmic, maternally inherited 12SrRNA point mutation (T1095C) was found in the pedigree. Respiratory chain enzyme analysis in cultured lymphocytes from the proband revealed a significant reduction in cytochrome c oxidase activity. Secondary structure predicts that this mutation disrupts a highly conserved loop in the small subunit ribosomal RNA, which is important in the initiation of mitochondrial protein synthesis. The mutation was not found in 270 controls of diverse ethnic origins. We conclude that this mutation is pathogenic and causes an oxidative phosphorylation defect by interfering with mitochondrial protein synthesis. Ann Neurol 2000;48:730–736