title: Renal Fanconi syndrome: taking a proximal look at the nephron.
abstract: Renal Fanconi syndrome (RFS) refers to the generalized dysfunction of the proximal tubule (PT) (Kleta R. Fanconi or not Fanconi? Lowe syndrome revisited. Clin J Am Soc Nephrol 2008; 3: 1244-1245). In its isolated form, RFS only affects the PT, but not the other nephron segments. The study of isolated RFS can thus provide specific insights into the function of the PT. In a recent paper, Klootwijk et al. investigated one such form of isolated RFS and revealed the underlying molecular basis (Klootwijk ED, Reichold M, Helip-Wooley A et al. Mistargeting of peroxisomal EHHADH and inherited renal Fanconi's syndrome. N Engl J Med 2014; 370: 129-138). The affected family had been described previously, demonstrating the typical features of RFS, such as low-molecular weight proteinuria, aminoaciduria, glycosuria and phosphaturia with consequent rickets; yet, importantly, patients had no evidence of impaired glomerular filtration (Tolaymat A, Sakarcan A, Neiberger R. Idiopathic Fanconi syndrome in a family. Part I. Clinical aspects. J Am Soc Nephrol 1992; 2: 1310-1317). Inheritance was consistent with an autosomal dominant mode. Klootwijk et al. discovered a surprising explanation: a heterozygous missense mutation causing partial mistargeting of the peroxisomal enzyme EHHADH to the mitochondria. Notably, disease causing was not the absence of the enzyme in the peroxisome, but its interference with mitochondrial function. The discovery of this novel disease mechanism not only confirmed the importance of mitochondrial function for PT transport, but also demonstrated the critical dependence of PT on fatty acid metabolism for energy generation.
authors.affiliation: Centre for Nephrology, University College London, London, UK.
authors.forename: Enriko D
authors.initials: ED
authors.lastname: Klootwijk
authors.affiliation: Medical Cell Biology, Institute of Physiology, Regensburg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Reichold
authors.affiliation: Division of Medicine, University College London, London, UK.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Unwin
authors.affiliation: Centre for Nephrology, University College London, London, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Kleta
authors.affiliation: Medical Cell Biology, Institute of Physiology, Regensburg, Germany.
authors.forename: Richard
authors.initials: R
authors.lastname: Warth
authors.affiliation: Centre for Nephrology, University College London, London, UK.
authors.forename: Detlef
authors.initials: D
authors.lastname: Bockenhauer
mesh_terms: D004272:DNA, Mitochondrial / Q000235:genetics; D005198:Fanconi Syndrome / Q000235:genetics / Q000473:pathology*; D006579:Heterozygote; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000473:pathology*; D020125:Mutation, Missense / Q000235:genetics; D063994:Peroxisomal Bifunctional Enzyme / Q000235:genetics
chemical_list: D004272:DNA, Mitochondrial; C576253:EHHADH protein, human; D063994:Peroxisomal Bifunctional Enzyme
keywords: EHHADH; acute kidney injury; proximal tubule; renal Fanconi syndrome