• Enriko D Klootwijk, Markus Reichold, Amanda Helip-Wooley, Asad Tolaymat, Carsten Broeker, Steven L Robinette, Joerg Reinders, Dominika Peindl, Kathrin Renner, Karin Eberhart, Nadine Assmann, Peter J Oefner, Katja Dettmer, Christina Sterner, Josef Schroeder, Niels Zorger, Ralph Witzgall, Stephan W Reinhold, Horia C Stanescu, Detlef Bockenhauer, Graciana Jaureguiberry, Holly Courtneidge, Andrew M Hall, Anisha D Wijeyesekera, Elaine Holmes, Jeremy K Nicholson, Kevin O'Brien, Isa Bernardini, Donna M Krasnewich, Mauricio Arcos-Burgos, Yuichiro Izumi, Hiroshi Nonoguchi, Yuzhi Jia, Janardan K Reddy, Mohammad Ilyas, Robert J Unwin, William A Gahl, Richard Warth, and Robert Kleta.
• From the Centre for Nephrology (E.D.K., H.C.S., D.B., G.J., H.C., A.M.H., R.J.U., R.K.) and Institute of Child Health (D.B., R.K.), University College London, and Biomolecular Medicine, Imperial College London (S.L.R., A.D.W., E.H., J.K.N.) - both in London; the Departments of Medical Cell Biology (M.R., C.B., D.P., C.S., R. Warth), Internal Medicine III (K.R.), Internal Medicine II (S.W.R.), and Molecular and Cellular Anatomy (R. Witzgall) and the Institutes of Functional Genomics (J.R., K.E., N.A., P.J.O., K.D.) and Pathology (J.S.), University of Regensburg, and the Department of Radiology, Barmherzige Brueder Hospital (N.Z.) - all in Regensburg, Germany; the National Human Genome Research Institute (A.H.-W., S.L.R., H.C.S., K.O., I.B., D.M.K., W.A.G., R.K.) and National Heart, Lung, and Blood Institute (Y.I.), National Institutes of Health, Bethesda, MD; the Division of Pediatric Nephrology, University of Florida, Jacksonville (A.T., M.I.); the Genome Biology Department, Australian National University, Canberra, ACT, Australia (M.A.-B.); Kitasato University Medical Center, Saitama, Japan (H.N.); and the Department of Pathology, Northwestern University, Chicago (Y.J., J.K.R.).
• N. Engl. J. Med.. 2014 Jan 9;370(2):129-38.

BackgroundIn renal Fanconi's syndrome, dysfunction in proximal tubular cells leads to renal losses of water, electrolytes, and low-molecular-weight nutrients. For most types of isolated Fanconi's syndrome, the genetic cause and underlying defect remain unknown.MethodsWe clinically and genetically characterized members of a five-generation black family with isolated autosomal dominant Fanconi's syndrome. We performed genomewide linkage analysis, gene sequencing, biochemical and cell-biologic investigations of renal proximal tubular cells, studies in knockout mice, and functional evaluations of mitochondria. Urine was studied with the use of proton nuclear magnetic resonance ((1)H-NMR) spectroscopy.ResultsWe linked the phenotype of this family's Fanconi's syndrome to a single locus on chromosome 3q27, where a heterozygous missense mutation in EHHADH segregated with the disease. The p.E3K mutation created a new mitochondrial targeting motif in the N-terminal portion of EHHADH, an enzyme that is involved in peroxisomal oxidation of fatty acids and is expressed in the proximal tubule. Immunocytofluorescence studies showed mistargeting of the mutant EHHADH to mitochondria. Studies of proximal tubular cells revealed impaired mitochondrial oxidative phosphorylation and defects in the transport of fluids and a glucose analogue across the epithelium. (1)H-NMR spectroscopy showed elevated levels of mitochondrial metabolites in urine from affected family members. Ehhadh knockout mice showed no abnormalities in renal tubular cells, a finding that indicates a dominant negative nature of the mutation rather than haploinsufficiency.ConclusionsMistargeting of peroxisomal EHHADH disrupts mitochondrial metabolism and leads to renal Fanconi's syndrome; this indicates a central role of mitochondria in proximal tubular function. The dominant negative effect of the mistargeted protein adds to the spectrum of monogenic mechanisms of Fanconi's syndrome. (Funded by the European Commission Seventh Framework Programme and others.).

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