Identification of G8969>A in mitochondrial ATP6 gene that severely compromises ATP synthase function in a patient...

Here we elucidated the pathogenesis of a 14-year-old Chinese female who initially developed an isolated nephropathy followed by a complex clinical presentation with brain and muscle problems, which indicated that the disease process was possibly due to a mitochondrial dysfunction. Careful evaluation of renal biopsy samples revealed a decreased staining of cells induced by COX and NADH dehydrogenase activities, and a strong fragmentation of the mitochondrial network. These anomalies were due to the presence of a mutation in the mitochondrial ATP6 gene, G8969>A. This mutation leads to replacement of a highly conserved serine residue at position 148 of the a-subunit of ATP synthase. Increasing the mutation load in cybrid cell lines was paralleled by the appearance of abnormal mitochondrial morphologies, diminished respiration and enhanced production of reactive oxygen species. An equivalent of the G8969>A mutation in yeast had dramatic consequences on ATP synthase, with a block in proton translocation. The mutation was particularly abundant (89%) in the kidney compared to blood and urine, which is likely the reason why this organ was affected first. Based on these findings, we suggest that nephrologists should pay more attention to the possibility of a mitochondrial dysfunction when evaluating patients suffering from kidney problems.