BACKGROUND: In 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. METHODS: We 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. RESULTS: We 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. CONCLUSIONS: Mistargeting 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.).
BACKGROUND: In 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. METHODS: We 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. RESULTS: We 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. CONCLUSIONS: Mistargeting 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.).
Authors: Markus Reichold; Enriko D Klootwijk; Joerg Reinders; Edgar A Otto; Mario Milani; Carsten Broeker; Chris Laing; Julia Wiesner; Sulochana Devi; Weibin Zhou; Roland Schmitt; Ines Tegtmeier; Christina Sterner; Hannes Doellerer; Kathrin Renner; Peter J Oefner; Katja Dettmer; Johann M Simbuerger; Ralph Witzgall; Horia C Stanescu; Simona Dumitriu; Daniela Iancu; Vaksha Patel; Monika Mozere; Mehmet Tekman; Graciana Jaureguiberry; Naomi Issler; Anne Kesselheim; Stephen B Walsh; Daniel P Gale; Alexander J Howie; Joana R Martins; Andrew M Hall; Michael Kasgharian; Kevin O'Brien; Carlos R Ferreira; Paldeep S Atwal; Mahim Jain; Alexander Hammers; Geoffrey Charles-Edwards; Chi-Un Choe; Dirk Isbrandt; Alberto Cebrian-Serrano; Ben Davies; Richard N Sandford; Christopher Pugh; David S Konecki; Sue Povey; Detlef Bockenhauer; Uta Lichter-Konecki; William A Gahl; Robert J Unwin; Richard Warth; Robert Kleta Journal: J Am Soc Nephrol Date: 2018-04-13 Impact factor: 10.121
Authors: Non Miyata; Janos Steffen; Meghan E Johnson; Sonia Fargue; Christopher J Danpure; Carla M Koehler Journal: Proc Natl Acad Sci U S A Date: 2014-09-18 Impact factor: 11.205
Authors: Oscar Rubio Cabezas; Sarah E Flanagan; Horia Stanescu; Elena García-Martínez; Richard Caswell; Hana Lango-Allen; Montserrat Antón-Gamero; Jesús Argente; Anna-Marie Bussell; Andre Brandli; Chris Cheshire; Elizabeth Crowne; Simona Dumitriu; Robert Drynda; Julian P Hamilton-Shield; Wesley Hayes; Alexis Hofherr; Daniela Iancu; Naomi Issler; Craig Jefferies; Peter Jones; Matthew Johnson; Anne Kesselheim; Enriko Klootwijk; Michael Koettgen; Wendy Lewis; José María Martos; Monika Mozere; Jill Norman; Vaksha Patel; Andrew Parrish; Celia Pérez-Cerdá; Jesús Pozo; Sofia A Rahman; Neil Sebire; Mehmet Tekman; Peter D Turnpenny; William Van't Hoff; Daan H H M Viering; Michael N Weedon; Patricia Wilson; Lisa Guay-Woodford; Robert Kleta; Khalid Hussain; Sian Ellard; Detlef Bockenhauer Journal: J Am Soc Nephrol Date: 2017-04-03 Impact factor: 10.121