Evolutional Analysis in Determining Pathogenic versus Nonpathogenic Mutations of ATPase 6 in Human Mitochondriopathy

A bstract : Because mitochondrial ATPase 6 plays an important role in ATP synthesis, mutations affecting ATPase 6 can undoubtedly cause human diseases. In contrast, the ATPase 6 gene is known to be a fast‐evolving gene and has generated enough polymorphisms to allow identity investigation for forensic casework. To investigate these seemingly opposite views, we analyzed amino acid sequences of ATPase 6 in at least 1,266 humans, 102 mammals, and 213 vertebrates. The result showed that the amino acids of human ATPase 6 could be divided into the following four groups. Amino acid residue 192 (affected by alteration at nt 9101) and 79 other residues were variable, and therefore substitutions of these residues would not be pathogenic. Amino acid residue 156 (affected by alteration at nt 8993) and 93 other residues were conserved in Homo sapiens , but not in Mammalia. Therefore, they were potentially pathogenic if altered. Function studies would be necessary to confirm their role in pathogenesis. Amino acid residue 217 (affected by alteration at nt 9176) and 9 other residues were conserved across all species, including S. cerevisiae and E. coli . Mutations involving these residues would be pathogenic, some of which might even be life threatening. The remainder (42 residues) were conserved in Mammalia, but not in yeast and E. coli . They were probably pathogenic if mutated. The classification proposed in this study may, therefore, provide an algorithm for a diagnostic approach when a newly identified change of ATPase 6 is suspected for human mitochondriopathy.