Mistargeting of peroxisomal EHHADH and inherited renal Fanconi's syndrome.
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Ошибки и ограничения
История · было → стало
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Klootwijk Enriko D, Reichold Markus, Helip-Wooley Amanda, Tolaymat Asad, Broeker Carsten, Robinette Steven L, Reinders Joerg, Peindl Dominika, Renner Kathrin, Eberhart Karin, Assmann Nadine, Oefner Peter J, Dettmer Katja, Sterner Christina, Schroeder Josef, Zorger Niels, Witzgall Ralph, Reinhold Stephan W, Stanescu Horia C, Bockenhauer Detlef, Jaureguiberry Graciana, Courtneidge Holly, Hall Andrew M, Wijeyesekera Anisha D, Holmes Elaine, Nicholson Jeremy K, O'Brien Kevin, Bernardini Isa, Krasnewich Donna M, Arcos-Burgos Mauricio, Izumi Yuichiro, Nonoguchi Hiroshi, Jia Yuzhi, Reddy Janardan K, Ilyas Mohammad, Unwin Robert J, Gahl William A, Warth Richard, Kleta Robert
Аннотация
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.).