Broadening the Spectrum of Diseases Related to Podocin Mutations

Abstract

Abstract. A total of 179 children with sporadic nephrotic syndrome were screened for podocin mutations: 120 with steroid resistance, and 59 with steroid dependence/frequent relapses. Fourteen steroid-resistant patients presented homozygous mutations that were associated with early onset of proteinuria and variable renal lesions, including one case with mesangial C3 deposition. Single mutations of podocin were found in four steroid-resistant and in four steroid-dependent; five patients had the same mutation (P20L). Among these, two had steroid/cyclosporin resistance, two had steroid dependence, and one responded to cyclosporin. 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. To further define the implication of R229Q, a familial case was characterized with two nephrotic siblings presenting the association of the R229Q with A297V mutation that were inherited from healthy mother and father, respectively. Immunohistochemistry with anti-podocin antibodies revealed markedly decreased expression of the protein in their kidneys. All carriers of heterozygous coding podocin mutation or R229Q were screened for nephrin mutation that was found in heterozygosity associated with R229Q in one patient. Finally, podocin loss of heterozygosity was excluded in one heterozygous child by characterizing cDNA from dissected glomeruli. These data outline the clinical features of sporadic nephrotic syndrome due to podocin mutations (homozygous and heterozygous) in a representative population with broad phenotype, including patients with good response to drugs. The pathogenetic implication of single podocin defects per se in proteinuria must be further investigated in view of the possibility that detection of a second mutation could have been missed. A suggested alternative is the involvement of other gene(s) or factor(s).

Recessive NPHS2 (Podocin) Mutations Are Rare in Adult-Onset Idiopathic Focal Segmental Glomerulosclerosis

“…This variant was absent in 54 white control subjects and was predicted to be probably pathogenic by the software PolyPhen (http://www.bork.embl-heidelberg.de/ PolyPhen/). In addition, we found several sequence variants of uncertain significance (A41G, E310K, E237Q, and IVS3 ϩ 3InsA) as well as several previously reported neutral polymorphisms (G102A, G34G, C288T, S96S, A242V, T954C, A318A, A1038G, and L346L) (27)(28)(29)(30)32). Among the entire study cohort, we found recessive mutations in only one patient.…”

“…Indeed, homozygous or compound heterozygous NPHS2 mutations have been documented in 30 to 46% of familial and 10 to 30% of sporadic steroid-resistant nephrotic syndrome in older children (26 -30). Typically, FSGS is the most common pathology associated with these cases, although a spectrum of glomerular lesions, including mesangial proliferation and minimal-change lesion, also may be seen (27,28). To define further the clinical relevance of NPHS2 mutations, we undertook a comprehensive mutation screening study in 87 cases of adult-onset idiopathic FSGS.…”

Short-Term Effects of Rituximab in Children with Steroid- and Calcineurin-Dependent Nephrotic Syndrome

“…Presence of pathological signs of cyclosporine nephropathy (tubulointerstitial fibrosis, epithelia vacuolization, calcineurin inhibitors crystals) (4) Deterioration of renal function in the last 6 months (20% increase of serum creatinine levels) NMR, nuclear magnetic resonance.…”

“…INS affects 2 to 2.7 new children per 100,000 children per year, in Western countries, with a prevalence of 16 cases per 100,000 children (1). Mechanisms underlying the disorder include different genetic and pathologic variants (2)(3)(4), with polymorphic podocyte injury as a unifying feature (5-7). All described phenotypes are considered part of a pathology continuum from minimal lesions (minimal change disease) to podocyte depletion and glomerulosclerosis (focal and segmental glomerular sclerosis) (7).…”

The Association of Podocin R229Q Polymorphism With Increased Albuminuria or Reduced Estimated GFR in a Large Population-Based Sample of US Adults

“…Abbreviations: BMI: body mass index, CHD: coronary heart disease, HDL: high-density lipoprotein cholesterol, ACR: albumin-to-creatinine ratio, eGFR: estimated glomerular filtration rate, NC. Covariates missing: hypertension (13), diabetes (14), BMI (4), smoking (7), CHD (72), HDL (7), triglycerides (7), ACR (31), eGFR (7). To convert HDL in mg/dl to mmol/l, multiply by 0.0259, triglycerides in mg/dl to mmol/l, multiply by 0.0113; eGFR in ml/min/1.73m 2 to ml/s, multiply by 0.0167.…”