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1.
J Am Soc Nephrol ; 29(7): 1849-1858, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29654216

RESUMEN

Background For many patients with kidney failure, the cause and underlying defect remain unknown. Here, we describe a novel mechanism of a genetic order characterized by renal Fanconi syndrome and kidney failure.Methods We clinically and genetically characterized members of five families with autosomal dominant renal Fanconi syndrome and kidney failure. We performed genome-wide linkage analysis, sequencing, and expression studies in kidney biopsy specimens and renal cells along with knockout mouse studies and evaluations of mitochondrial morphology and function. Structural studies examined the effects of recognized mutations.Results The renal disease in these patients resulted from monoallelic mutations in the gene encoding glycine amidinotransferase (GATM), a renal proximal tubular enzyme in the creatine biosynthetic pathway that is otherwise associated with a recessive disorder of creatine deficiency. In silico analysis showed that the particular GATM mutations, identified in 28 members of the five families, create an additional interaction interface within the GATM protein and likely cause the linear aggregation of GATM observed in patient biopsy specimens and cultured proximal tubule cells. GATM aggregates-containing mitochondria were elongated and associated with increased ROS production, activation of the NLRP3 inflammasome, enhanced expression of the profibrotic cytokine IL-18, and increased cell death.Conclusions In this novel genetic disorder, fully penetrant heterozygous missense mutations in GATM trigger intramitochondrial fibrillary deposition of GATM and lead to elongated and abnormal mitochondria. We speculate that this renal proximal tubular mitochondrial pathology initiates a response from the inflammasome, with subsequent development of kidney fibrosis.


Asunto(s)
Amidinotransferasas/genética , Síndrome de Fanconi/genética , Fallo Renal Crónico/genética , Mitocondrias/metabolismo , Mitocondrias/patología , Anciano , Amidinotransferasas/metabolismo , Animales , Simulación por Computador , Síndrome de Fanconi/complicaciones , Síndrome de Fanconi/metabolismo , Síndrome de Fanconi/patología , Femenino , Heterocigoto , Humanos , Lactante , Inflamasomas/metabolismo , Fallo Renal Crónico/etiología , Fallo Renal Crónico/metabolismo , Fallo Renal Crónico/patología , Masculino , Ratones , Ratones Noqueados , Conformación Molecular , Mutación , Mutación Missense , Linaje , Especies Reactivas de Oxígeno/metabolismo , Análisis de Secuencia de ADN , Adulto Joven
2.
N Engl J Med ; 370(2): 129-38, 2014 Jan 09.
Artículo en Inglés | MEDLINE | ID: mdl-24401050

RESUMEN

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.).


Asunto(s)
Síndrome de Fanconi/genética , Túbulos Renales Proximales/metabolismo , Mitocondrias/metabolismo , Mutación Missense , Enzima Bifuncional Peroxisomal/genética , Secuencia de Aminoácidos , Animales , Población Negra , Cromosomas Humanos Par 3 , Modelos Animales de Enfermedad , Síndrome de Fanconi/etnología , Femenino , Ligamiento Genético , Humanos , Masculino , Ratones , Ratones Noqueados , Datos de Secuencia Molecular , Linaje , Enzima Bifuncional Peroxisomal/química , Enzima Bifuncional Peroxisomal/metabolismo , Fenotipo , Análisis de Secuencia de ADN
3.
Cell Rep ; 15(7): 1423-1429, 2016 05 17.
Artículo en Inglés | MEDLINE | ID: mdl-27160910

RESUMEN

We recently reported an autosomal dominant form of renal Fanconi syndrome caused by a missense mutation in the third codon of the peroxisomal protein EHHADH. The mutation mistargets EHHADH to mitochondria, thereby impairing mitochondrial energy production and, consequently, reabsorption of electrolytes and low-molecular-weight nutrients in the proximal tubule. Here, we further elucidate the molecular mechanism underlying this pathology. We find that mutated EHHADH is incorporated into mitochondrial trifunctional protein (MTP), thereby disturbing ß-oxidation of long-chain fatty acids. The resulting MTP deficiency leads to a characteristic accumulation of hydroxyacyl- and acylcarnitines. Mutated EHHADH also limits respiratory complex I and corresponding supercomplex formation, leading to decreases in oxidative phosphorylation capacity, mitochondrial membrane potential maintenance, and ATP generation. Activity of the Na(+)/K(+)-ATPase is thereby diminished, ultimately decreasing the transport activity of the proximal tubule cells.


Asunto(s)
Síndrome de Fanconi/metabolismo , Riñón/metabolismo , Riñón/patología , Mitocondrias/metabolismo , Enfermedades Mitocondriales/metabolismo , Animales , Transporte Biológico , Extractos Celulares , Metabolismo Energético , Síndrome de Fanconi/complicaciones , Síndrome de Fanconi/patología , Ácidos Grasos/metabolismo , Células LLC-PK1 , Microscopía Confocal , Enfermedades Mitocondriales/complicaciones , Enfermedades Mitocondriales/patología , Mutación/genética , Oxidación-Reducción , Enzima Bifuncional Peroxisomal/metabolismo , Proteómica , ATPasa Intercambiadora de Sodio-Potasio/metabolismo , Fracciones Subcelulares/metabolismo , Porcinos
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