Severe lactic acidosis caused by a novel frame-shift mutation in mitochondrial-encoded cytochrome c oxidase subunit II

We report the first frame-shift truncation mutation in a mitochondrial DNA (mtDNA)-encoded subunit II of cytochrome c oxidase (COXII). The mutation wa s identified by temporal temperature gradient gel electrophoresis (TTGE) fo llowed by direct DNA sequencing in an infant who died at 12 days of age fol lowing a course of apnea, bradycardia, and severe lactic acidosis. The pati ent had a twin brother who died at two days of age of similar course. The m utation, 8042delAT, produced a truncated protein that was 72 amino acids sh orter than the wild type protein. The mutant protein, missing one third of the amino acid residues at the C-terminal essential for hydrophilic interac tion with cytochrome c, ligand binding to Cu-A and Mg, and the formation of proton and water channels, apparently has devastating effects on mitochond rial respiratory function. Published 2001 Wiley-Liss, Inc.(dagger).