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.