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.
Because NPHS2 mutations were found in nearly 30% of these patients with "sporadic" SRINS, mutational analysis should also be performed in these patients.
In vitro permeability activity (P(alb)) was determined in sera of five patients with autosomal recessive steroid-resistant nephrotic syndrome (NPHS2), an inherited condition indistinguishable from idiopathic FSGS on clinical grounds, but in which proteinuria is determined by homozygous mutations of podocin, a key component of the glomerular podocyte.
The levels of Podocin, the gene mutated in autosomal recessive steroid-resistant nephrotic syndrome (NPHS2), and Nephrin, the gene mutated in congenital nephrotic syndrome of the Finnish type (NPHS1), are slightly reduced in kr(enu)/kr(enu) podocytes.
Ten children with non-familial steroid-resistant nephrotic syndrome along with focal-segmental glomerulosclerosis were tested for mutations in the WT-1 and NPHS2 genes.
We isolated genomic DNA from 36 Japanese children with chronic renal insufficiency caused by SRNS or heavy proteinuria, and analyzed all eight exons and exon-intron boundaries of NPHS2 using the polymerase chain reaction and direct sequencing.
Familial forms of focal segmental glomerulosclerosis (FSGS) are caused by mutations in genes at 1q25-31 (gene for steroid-resistant nephrotic syndrome 2 [NPHS2]), 11q21-22, 19q13 (gene for alpha-actinin 4 and NPHS1), and at additional unidentified chromosomal loci.
We generated podocin-deficient (Nphs2-/-) mice to investigate the function of podocin, a protein expressed at the insertion of the slit diaphragm in podocytes and defective in a subset of patients with steroid-resistant nephrotic syndrome and focal and segmental glomerulosclerosis.
Genetic mutations in the NPHS2 gene, which encodes podocin, recently have been shown to be strongly associated with a recessive form of steroid-resistant nephrotic syndrome.
NPHS2 mutation analysis was performed in 338 patients from 272 families with SRNS: 81 families with AR SRNS, 172 patients with sporadic SRNS, and 19 patients with diffuse mesangial sclerosis (DMS).
It is now well recognized that podocin mutations are found in 10%-30% of sporadic cases of steroid-resistant nephrotic syndrome with focal segmental glomerulosclerosis.
A heterozygous missense mutation of L361P in exon 8 of NPHS2 was detected in one of 23 children with sporadic SRNS, whereas it was not found in 53 controls.
Mutations in the podocin gene, NPHS2, have been shown in familial and sporadic forms of steroid-resistant nephrotic syndrome, including focal segmental glomerulosclerosis.