Renal Fanconi syndromes are a generalized inherited or acquired dysfunction of the renal proximal tubules. In a family with an inherited autosomal dominant form of renal Fanconi syndrome, a heterozygous mutation was found in a gene we named Fanconi Associated Protein (FAP). The mutation of FAP leads to a de-novo formation of a mitochondrial targeting motif and, as a consequence, to an impaired mitochondrial function.

To assess the pathomechanism of this mutation, an inducible proximal tubular cell model was generated. Immunohistochemical analysis of these cells revealed mistargeting of the mutant FAP into mitochondria. Resorufin arsenical helix binder (ReAsh) labeled FAP was shown to be located in the mitochondrial matrix when using electron microscopy. Western blots of mutated FAP revealed that the targeting motif was cleaved once the protein was imported into the mitochondria.

We hypothesized that mutated FAP interferes with oxidative phosphorylation by interacting with a homologous mitochondrial protein involved in ATP production. This was confirmed by a co-immunoprecipitation, where mutated FAP was successfully pulled down with an antibody against the homologous mitochondrial protein. Furthermore, over-expression of mutated FAP led to a diminished ATP production in our cell model. Thus, we propose that this form of renal Fanconi syndrome is caused by insufficient generation of ATP by the proximal tubules resulting in an inability to maintain high-energy demanding transport processes. To our knowledge, this is the first description of a genetic defect leading to intracellular mistargeting of a mutant protein resulting in a mitochondrial pathology.