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.
The interethnic differences in the occurrence of NPHS2 mutations may explain, in part, the previous observation that Arab patients with FSGS in Israel have a worse prognosis as compared with Jewish patients, despite similar presenting symptoms and medical management.
We confirm an overlap in the NPHS1/NPHS2 mutation spectrum with the characterization of a unique di-genic inheritance of NPHS1 and NPHS2 mutations, which results in a 'tri-allelic' hit and appears to modify the phenotype from CNF to one of congenital focal segmental glomerulosclerosis (FSGS).
Identification of R229Q mutations may be of clinical importance, as NPHS2-associated disease appears to define a subgroup of FSGS patients unresponsive to corticosteroids.
Identification of R229Q mutations may be of clinical importance, as NPHS2-associated disease appears to define a subgroup of FSGS patients unresponsive to corticosteroids.
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.
NPHS2 mutations are responsible for autosomal recessive familial steroid-resistant nephrotic syndrome (SRNS) with minor glomerular abnormalities or focal segmental glomerulosclerosis (FSGS), which is characterized by early childhood onset (age less than 6 years) and rapid progression to chronic renal insufficiency.
Mutations in both podocin gene (NPHS2) alleles lead to a wide range of human disease, from childhood-onset steroid-resistant FSGS and minimal change disease to adult-onset FSGS.
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.
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.
Among 42 patients, podocin was normally expressed in glomeruli in purpura nephritis, IgA nephropathy (IgAN), and minimal-change disease (MCD), while it was either decreased or absent in most subjects with focal segmental glomerulosclerosis (FSGS).
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.
Among 32 patients with two NPHS2 mutations who underwent kidney transplantation, only one developed late recurrence of focal segmental glomerulosclerosis (FSGS).
NPHS2 mutations are responsible for autosomal recessive familial focal segmental glomerulosclerosis (FSGS), and these mutations were detected in both familial and sporadic forms of FSGS.
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.
On the contrary, podocin expression was unchanged after incubation with serum and PF from FSGS patients for short periods, but markedly reduced at 24 h. Our results demonstrate that serum and PF from FSGS patients may directly affect nephrin and podocin in human podocytes, thus providing new insights into the mechanisms causing proteinuria in FSGS.
Large multicenter studies demonstrated that patients with two pathogenic NPHS2 mutations have a very low risk of recurring FSGS after renal transplantation, whereas patients with only one mutation presumably have a risk comparable to non-NPHS2FSGS patients.
Mutations in the podocin gene, NPHS2, have been shown in familial and sporadic forms of steroid-resistant nephrotic syndrome, including focal segmental glomerulosclerosis.
The close temporal relationship of FSGS recurrence with CsA withdrawal and conversion to SRL suggests that caution should be exercised in the use of CsA-free immunosuppression also in patients with NPHS2-associated FSGS.