title: Broadening the spectrum of diseases related to podocin mutations.
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).
authors.affiliation: Laboratory on Pathophysiology of Uremia, Istituto G. Gaslini, 16148 Genoa, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Caridi
authors.forename: Roberta
authors.initials: R
authors.lastname: Bertelli
authors.forename: Marco
authors.initials: M
authors.lastname: Di Duca
authors.forename: Monica
authors.initials: M
authors.lastname: Dagnino
authors.forename: Francesco
authors.initials: F
authors.lastname: Emma
authors.forename: Andrea
authors.initials: A
authors.lastname: Onetti Muda
authors.forename: Francesco
authors.initials: F
authors.lastname: Scolari
authors.forename: Nunzia
authors.initials: N
authors.lastname: Miglietti
authors.forename: Gianna
authors.initials: G
authors.lastname: Mazzucco
authors.forename: Luisa
authors.initials: L
authors.lastname: Murer
authors.forename: Alba
authors.initials: A
authors.lastname: Carrea
authors.forename: Laura
authors.initials: L
authors.lastname: Massella
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Rizzoni
authors.forename: Francesco
authors.initials: F
authors.lastname: Perfumo
authors.forename: Gian Marco
authors.initials: GM
authors.lastname: Ghiggeri
mesh_terms: D000185:Actinin / Q000235:genetics; D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D005923:Glomerulosclerosis, Focal Segmental / Q000453:epidemiology / Q000235:genetics; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D015994:Incidence; D007223:Infant; D007231:Infant, Newborn; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008840:Microfilament Proteins; D009404:Nephrotic Syndrome / Q000453:epidemiology / Q000235:genetics*; D010641:Phenotype; D011506:Proteins / Q000235:genetics; D011507:Proteinuria / Q000453:epidemiology / Q000235:genetics
chemical_list: C111453:ACTN4 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D008840:Microfilament Proteins; C407223:NPHS2 protein; D011506:Proteins; C113267:nephrin; D000185:Actinin