NPHS2 (podicin) mutations in Turkish children with idiopathic nephrotic syndrome

Abstract

The podocin (NPHS2) gene encodes podocin protein, which has an important role in glomerular ultrafiltration and controlling slit membrane permeability. The detection of an NPHS2 mutation affects the treatment plan for children with nephritic syndrome (NS). The frequency and spectrum of podocin mutations in the Turkish population have remained largely unknown. The aim of this study was to screen for podocin mutations in Turkish patients with steroid-resistant NS (SRNS) and to compare it with other published series. There were 295 children with SRNS, originating from Turkey, included in this study. Forty-one patients (13.8%) had familial NS and 254 patients (86.2%) had sporadic NS. Mutation analysis was performed in all eight exons of the NPHS2 gene with the direct DNA sequencing method. There were 53 different pathogenetic NPHS2 mutations detected, including 37 novel mutations. The mutation detection rate was 24.7% for all patients, 29.2% for familial, and 24% for sporadic SRNS. The most common mutated exon was exon 5 (52 allele). The presence of mutations in exon 4 was found to increase the risk of end-stage renal disease (ESRD). Among patients with mutations, the rates of renal failure and/or ESRD (26%) were significantly higher than in those without mutations (12.6%). The mean time of progression to renal failure and ESRD in patients with mutations (1.8 +/- 2.5 years) was significantly shorter than in patients without mutations (3.7 +/- 4.0 years). Additionally, in patients with heterozygote mutations, fewer cases (13.6%) progressed to renal failure and/or ESRD than in with patients who had homozygote/compound heterozygote mutations (31.3%). In conclusion, podocin mutations are responsible for some of both familial and sporadic SRNS cases in Turkey. The mutations in this gene should be searched for in every child after presentation with the first episode of NS.

Heterogeneous Genetic Alterations in Sporadic Nephrotic Syndrome Associate with Resistance to Immunosuppression

“…More specifically, in five patients, we observed different variants in the NPHS2 gene (two homozygous and three compound heterozygous) that were already described as potentially pathogenic. [16][17][18][19][20] In patient 1, we observed the non-neutral polymorphic variant -52 C.G, which was previously reported to reduce NPHS2 transcription by abolishing the binding of the regulatory factor upstream transcription factor 1 (USF1) to the NPHS2 promoter. 16 This patient was homozygous, having inherited the two variants from each of two nonaffected parents, and displayed a significantly reduced podocin expression at the biopsy (Supplemental Figure 1), even if he was affected by a minimal change disease, where levels of podocin are usually normal.…”

A Disease-causing Mutation Illuminates the Protein Membrane Topology of the Kidney-expressed Prohibitin Homology (PHB) Domain Protein Podocin

“…Mutations of this proline residue are known causes of protein dysfunction throughout species. A P134S mutation in MEC-2 (MEC-2 P134S ) causes touch insensitivity in the nematode (22), and the equivalent P118L mutation in humans causes SRNS (3,4,20,21). Because it has been shown that a mutation of this conserved proline in stomatin (P47S) changes the membrane topology of stomatin (31), we concentrated on the molecular mechanisms that cause SRNS in patients bearing the podocin mutation P118L (corresponding to P120L in the mouse protein, collectively named podocin P3 L hereafter).…”

Mutation-dependent recessive inheritance of NPHS2-associated steroid-resistant nephrotic syndrome

“…[Arg229Gln];[mut] that causes SRNS with a median age at diagnosis of 13 years (range, 0-39 years) and progression to ESRD by 26 years (range, 10-50 years) 7,[13][14][15][16][17][18] . Nevertheless, the p.Arg229Gln variant in the homozygous state does not cause SRNS 19,20 .…”

“…[Arg229Gln]; [mut] in 318 families from French and other SRNS cohorts [13][14][15][16][17][18] and found a striking difference (P = 1.2 × 10−35; Table 1). Notably, whereas mutations in the last two exons (7 and 8) were rare in cases with [ Out of the 56 mutations located in exons 1-6, only 4 were associated with p.Arg229Gln in cases with SRNS, and these accounted for only 8 of 71 (11%) total p.Arg229Gln-associated alleles (Tables 1 and 2) Table 2).…”