Prevalence, genetics, and clinical features of patients carrying podocin mutations in steroid-resistant nonfamilial focal segmental glomerulosclerosis

Podocin mutations (NPHS2 gene) are responsible for the autosomal recessive form of steroid-resistant nephrotic syndrome. As a result of a screening fo r these gene alterations in a cohort of Italian patients with nonfamilial n ephrotic syndrome and histologic focal segmental glomerulosclerosis (FSGS). nine patients with NPHS2 gene homozygous or composite heterozygous mutatio ns were found. In addition to the previously described defects, two novel m utations at exon 4 were identified (frameshift, L169P); four single nucleot ide 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. Pat ients carrying NPHS2 mutations and without a family history of nephrotic sy ndrome were indistinguishable from those with idiopathic FSGS on the basis of the clinical phenotype. Two of the nine patients had normal renal functi on at 3 and 10 yr of age. despite the presence of the nephrotic syndrome. T he 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 bef ore and after transplantation were similar, including the age at onset, the amount of proteinuria, and the absence of any response to steroids and oth er immunosuppressants. Finally, two children presented recurrence of mild p roteinuria after transplantation, which promptly remitted after plasmaphere sis combined with cyclophosphamide. These data demonstrate that podocin mut ations in nonfamilial cases of steroid-resistant nephrotic syndrome are fre quent and may be due in one case to a founder effect. The pretransplantatio n 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 pl asmapheresis. These observations support a role of molecular screening of t he podocin gene in patients with nephrotic syndrome before immunosuppressiv e treatment is started.