The Renal Fanconi Syndrome is characterized by reduced transport capacity of the proximal tubule leading to glucosuria, aminoaciduria, phosphaturia, small molecular weight proteinuria and a metabolic acidosis. Genetic investigation of a family with autosomal dominant inherited Fanconi syndrome revealed a mutation in a peroxisomal gene that we named Fanconi associated protein (FAP). The N-terminal mutation leads to the formation of a mitochondrial targeting sequence and subsequent mistargeting of FAP. Functional impact of the mutation was investigated using an inducible proximal tubular cell line containing either wildtype FAP or mutated FAP.

Immunohistochemical analysis confirmed correct localization of wildtype FAP in peroxisomes and mistargeting of mutated FAP to the mitochondria. Measurement of metabolites in the medium showed a faster decrease in glucose concentration in the medium of cells with mutated FAP compared to cells overexpressing wildtype FAP pointing towards an increased glycolytic activity in these cells. Furthermore, lactate/pyruvate ratio was elevated in the medium of cells overexpressing mutated FAP which is highly indicative of a mitochondrial dysfunction. Additionally, activity of the respiratory chain was evaluated using high-resolution respirometry. These measurements showed reduced oxidative phosphorylation capacity upon stimulation.

FAP knockout mice did not exhibit any proximal tubular transport defect as established by amino acid analysis using GC-MS. According to our hypothesis, mistargeting of mutated FAP to the mitochondria rather than a lack of FAP in peroxisomes leads to reduced ATP generation caused by impaired oxidative phosphorylation in affected cells. As a consequence, ATP-dependent reabsorption of metabolites in renal proximal tubule cells is reduced.