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Broadening the Spectrum of Diseases Related to Podocin Mutations

Gianluca Caridi^*, Roberta Bertelli^*, Marco Di Duca^*, Monica Dagnino^*, Francesco Emma, Andrea Onetti Muda, Francesco Scolari^¶, Nunzia Miglietti^||, Gianna Mazzucco^#, Luisa Murer^@, Alba Carrea^*, Laura Massella, Gianfranco Rizzoni, Francesco Perfumo and Gian Marco Ghiggeri^*,

*Laboratory on Pathophysiology of Uremia, and Department of Nephrology, Istituto G. Gaslini, Genova, Italy; Section of Nephrology, Bambin Gesù Children Hospital, Rome, Italy; Department of Experimental Medicine and Pathology, University "La Sapienza," Rome, Italy; ^¶Unit of Nephrology, Spedali Civili di Brescia, Italy; ^||Department of Pediatrics, University of Brescia, Italy; ^#Pathology Section, Department of Biomedical Sciences and Human Oncology, University of Torino, Italy; ^@Department of Pediatrics, University of Padova, Italy.

Correspondence to Dr. Gian Marco Ghiggeri, Laboratorio di Fisiopatologia dell’Uremia, Istituto G. Gaslini, 16148 Genova, Italy. Phone: 39-010-380742; Fax: 39-010-395214;

ABSTRACT. A total of 179 children with sporadic nephrotic syndrome were screened for podocin mutations: 120 with steroid resistance, and 59 with steroid dependence/frequent relapses. Fourteen steroid-resistant patients presented homozygous mutations that were associated with early onset of proteinuria and variable renal lesions, including one case with mesangial C3 deposition. Single mutations of podocin were found in four steroid-resistant and in four steroid-dependent; five patients had the same mutation (P20L). Among these, two had steroid/cyclosporin resistance, two had steroid dependence, and one responded to cyclosporin. The common variant R229Q of podocin, recently associated with late-onset focal segmental glomerulosclerosis, had an overall allelic frequency of 4.2% versus 2.5% in controls. To further define the implication of R229Q, a familial case was characterized with two nephrotic siblings presenting the association of the R229Q with A297V mutation that were inherited from healthy mother and father, respectively. Immunohistochemistry with anti-podocin antibodies revealed markedly decreased expression of the protein in their kidneys. All carriers of heterozygous coding podocin mutation or R229Q were screened for nephrin mutation that was found in heterozygosity associated with R229Q in one patient. Finally, podocin loss of heterozygosity was excluded in one heterozygous child by characterizing cDNA from dissected glomeruli. These data outline the clinical features of sporadic nephrotic syndrome due to podocin mutations (homozygous and heterozygous) in a representative population with broad phenotype, including patients with good response to drugs. The pathogenetic implication of single podocin defects per se in proteinuria must be further investigated in view of the possibility that detection of a second mutation could have been missed. A suggested alternative is the involvement of other gene(s) or factor(s). E-mail: labnefro@ospedale-gaslini.ge.it

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