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TRANSLATIONAL PHYSIOLOGY

Combined proteomic and metabonomic studies in three genetic forms of the renal Fanconi syndrome

¹Ludwig Institute for Cancer Research and Department of Biochemistry and Molecular Biology and ²Centre for Nephrology and Department of Physiology, University College London, London; ³Department of Biomolecular Medicine, Division of Surgery, Oncology, Reproductive Biology, and Anaesthetics, Faculty of Medicine, Imperial College London, London; ⁴Clinical Biochemistry, Addenbrooke's Hospital, Cambridge, United Kingdom; ⁵Chair of Nephrology, Second University of Naples, Naples; and ⁶Center of Mass Spectrometry, Proteomics, and Bioinformatics, Institute of Food Science, Consiglio Nazionale Delle Ricerche, Avellino, Italy

Submitted 23 February 2007 ; accepted in final form 8 May 2007

The renal Fanconi syndrome is a defect of proximal tubular function causing aminoaciduria and low-molecular-weight proteinuria. Dent's disease and Lowe syndrome are defined X-linked forms of Fanconi syndrome; there is also an autosomal dominant idiopathic form (ADIF), phenotypically similar to Dent's disease though its gene defect is still unknown. To assess whether their respective gene products are ultimately involved in a common reabsorptive pathway for proteins and low-molecular-mass endogenous metabolites, we compared renal Fanconi urinary proteomes and metabonomes with normal (control) urine using mass spectrometry and ¹H-NMR spectroscopy, respectively. Urine from patients with low-molecular-weight proteinuria secondary to ifosfamide treatment (tubular proteinuria; TP) was also analyzed for comparison. All four of the disorders studied had characteristic proteomic and metabonomic profiles. Uromodulin was the most abundant protein in normal urine, whereas Fanconi urine was dominated by albumin. ¹H-NMR spectroscopic data showed differences in the metabolic profiles of Fanconi urine vs. normal urine, due mainly to aminoaciduria. There were differences in the urinary metabolite and protein compositions between the three genetic forms of Fanconi syndrome: cluster analysis grouped the Lowe and Dent's urinary proteomes and metabonomes together, whereas ADIF and TP clustered together separately. Our findings demonstrate a distinctive "polypeptide and metabolite fingerprint" that can characterize the renal Fanconi syndrome; they also suggest that more subtle and cause-specific differences may exist between the different forms of Fanconi syndrome that might provide novel insights into the underlying mechanisms and cellular pathways affected.

kidney; urine; mass spectrometry; NMR

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