title: Prevalence, genetics, and clinical features of patients carrying podocin mutations in steroid-resistant nonfamilial focal segmental glomerulosclerosis.
abstract: Podocin mutations (NPHS2 gene) are responsible for the autosomal recessive form of steroid-resistant nephrotic syndrome. As a result of a screening for these gene alterations in a cohort of Italian patients with nonfamilial nephrotic syndrome and histologic focal segmental glomerulosclerosis (FSGS), nine patients with NPHS2 gene homozygous or composite heterozygous mutations were found. In addition to the previously described defects, two novel mutations at exon 4 were identified (frameshift, L169P); four single nucleotide polymorphisms (SNPs) and one dinucleotide repeat were also identified. On the basis of haplotype analysis, a founder effect was suggested for the 419delG mutation, the most frequently observed in the patients studied. Patients carrying NPHS2 mutations and without a family history of nephrotic syndrome were indistinguishable from those with idiopathic FSGS on the basis of the clinical phenotype. Two of the nine patients had normal renal function at 3 and 10 yr of age, despite the presence of the nephrotic syndrome. The other seven had reached end-stage renal failure at a mean age of 9.6 yr (range, 4 to 17 yr) and had received renal allografts. In those presenting with end-stage renal failure, the clinical and laboratory features both before and after transplantation were similar, including the age at onset, the amount of proteinuria, and the absence of any response to steroids and other immunosuppressants. Finally, two children presented recurrence of mild proteinuria after transplantation, which promptly remitted after plasmapheresis combined with cyclophosphamide. These data demonstrate that podocin mutations in nonfamilial cases of steroid-resistant nephrotic syndrome are frequent and may be due in one case to a founder effect. The pretransplantation and posttransplantation outcomes in the group of patients with mutations of the podocin gene are similar to classical idiopathic FSGS, including the possibility of recurrence of proteinuria that is mild and responsive to plasmapheresis. These observations support a role of molecular screening of the podocin gene in patients with nephrotic syndrome before immunosuppressive treatment is started.
authors.affiliation: *Laboratory and Unit of Nephrology and Laboratory of Molecular Genetics, Istituto Giannina Gaslini, Genoa, Italy; and Istituto di Medicina Clinica, University of Trieste, Trieste, Italy.
authors.forename: Gianluca
authors.initials: G
authors.lastname: Caridi
authors.affiliation: *Laboratory and Unit of Nephrology and Laboratory of Molecular Genetics, Istituto Giannina Gaslini, Genoa, Italy; and Istituto di Medicina Clinica, University of Trieste, Trieste, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Bertelli
authors.affiliation: *Laboratory and Unit of Nephrology and Laboratory of Molecular Genetics, Istituto Giannina Gaslini, Genoa, Italy; and Istituto di Medicina Clinica, University of Trieste, Trieste, Italy.
authors.forename: Alba
authors.initials: A
authors.lastname: Carrea
authors.affiliation: *Laboratory and Unit of Nephrology and Laboratory of Molecular Genetics, Istituto Giannina Gaslini, Genoa, Italy; and Istituto di Medicina Clinica, University of Trieste, Trieste, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Di Duca
authors.affiliation: *Laboratory and Unit of Nephrology and Laboratory of Molecular Genetics, Istituto Giannina Gaslini, Genoa, Italy; and Istituto di Medicina Clinica, University of Trieste, Trieste, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Catarsi
authors.affiliation: *Laboratory and Unit of Nephrology and Laboratory of Molecular Genetics, Istituto Giannina Gaslini, Genoa, Italy; and Istituto di Medicina Clinica, University of Trieste, Trieste, Italy.
authors.forename: Mary
authors.initials: M
authors.lastname: Artero
authors.affiliation: *Laboratory and Unit of Nephrology and Laboratory of Molecular Genetics, Istituto Giannina Gaslini, Genoa, Italy; and Istituto di Medicina Clinica, University of Trieste, Trieste, Italy.
authors.forename: Michele
authors.initials: M
authors.lastname: Carraro
authors.affiliation: *Laboratory and Unit of Nephrology and Laboratory of Molecular Genetics, Istituto Giannina Gaslini, Genoa, Italy; and Istituto di Medicina Clinica, University of Trieste, Trieste, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Zennaro
authors.affiliation: *Laboratory and Unit of Nephrology and Laboratory of Molecular Genetics, Istituto Giannina Gaslini, Genoa, Italy; and Istituto di Medicina Clinica, University of Trieste, Trieste, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Candiano
authors.affiliation: *Laboratory and Unit of Nephrology and Laboratory of Molecular Genetics, Istituto Giannina Gaslini, Genoa, Italy; and Istituto di Medicina Clinica, University of Trieste, Trieste, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Musante
authors.affiliation: *Laboratory and Unit of Nephrology and Laboratory of Molecular Genetics, Istituto Giannina Gaslini, Genoa, Italy; and Istituto di Medicina Clinica, University of Trieste, Trieste, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Seri
authors.affiliation: *Laboratory and Unit of Nephrology and Laboratory of Molecular Genetics, Istituto Giannina Gaslini, Genoa, Italy; and Istituto di Medicina Clinica, University of Trieste, Trieste, Italy.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Ginevri
authors.affiliation: *Laboratory and Unit of Nephrology and Laboratory of Molecular Genetics, Istituto Giannina Gaslini, Genoa, Italy; and Istituto di Medicina Clinica, University of Trieste, Trieste, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Perfumo
authors.affiliation: *Laboratory and Unit of Nephrology and Laboratory of Molecular Genetics, Istituto Giannina Gaslini, Genoa, Italy; and Istituto di Medicina Clinica, University of Trieste, Trieste, Italy.
authors.forename: Gian Marco
authors.initials: GM
authors.lastname: Ghiggeri
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D004351:Drug Resistance; D005260:Female; D005787:Gene Frequency; D005819:Genetic Markers; D005923:Glomerulosclerosis, Focal Segmental / Q000188:drug therapy* / Q000235:genetics* / Q000503:physiopathology; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation / Q000502:physiology*; D012008:Recurrence; D013256:Steroids / Q000627:therapeutic use*
chemical_list: D005819:Genetic Markers; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein; D013256:Steroids