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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2013  |  Volume : 24  |  Issue : 6  |  Page : 1210-1213
Does NPHS1 polymorphism modulate P118l mutation in NPHS2?

Department of Pediatric Nephrology, Ege University Faculty of Medicine, Bornova, Izmir, Turkey

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Date of Web Publication13-Nov-2013


Nephrotic syndrome (NS) in the first year of life is uncommon and makes up a heterogeneous group of disorders. Subsequent studies have further defined the phenotype associated with mutations in the NPHS2 gene, revealing that patients usually develop NS from birth to 6 years of age. We report a child aged 4 months with steroid-resistant NS who had polymorphism of NPHS1 (E117K) and mutation of NPHS2 (P118L). Our patient was carrying a polymorphic NPHS1 mutation, while phenotypically she had a poor prognostic NPHS2 mutation. However, it must be questioned whether this polymorphic change (E117K) alters the signaling pathways of the podocytes and leads to P118L mutation, thus making it behave differently. Perhaps, this would be called a genetic modifier in future.

How to cite this article:
Dincel N, Mir S, Berdeli A, Bulut IK, Sozeri B. Does NPHS1 polymorphism modulate P118l mutation in NPHS2?. Saudi J Kidney Dis Transpl 2013;24:1210-3

How to cite this URL:
Dincel N, Mir S, Berdeli A, Bulut IK, Sozeri B. Does NPHS1 polymorphism modulate P118l mutation in NPHS2?. Saudi J Kidney Dis Transpl [serial online] 2013 [cited 2021 Mar 1];24:1210-3. Available from: https://www.sjkdt.org/text.asp?2013/24/6/1210/121300

   Introduction Top

Nephrotic syndrome (NS) is uncommon in the first year of life and makes up a heterogeneous group of disorders. When onset is under 3 months of age, it is defined as congenital NS, and when it is between 4 and 12 months of age, it is called infantile NS. Most cases in this age group are attributed to genetic causes, the majority being mutations in the gene encoding nephrin (NPHS1). Nephrin is linked to actin cytoskeleton via an adaptor protein Nck and phosphoinositide 3-kinase (PI3K) and, thus, has a regulatory role in actin cyto skeleton and podocyte morphology. [1],[2],[3] Mutations in other genes encoding podocyte slit diaphragm (SD) proteins, such as podocin, which does encoding of the podocin gene (NPHS2), can also cause early-onset NS. [4] Together with the fact that nephrin has a role in the signaling process of the podocyte cell, podocin is necessary for proper targeting of nephrin into the SD. This interrelation can explain the distorted nephrin expression in the central nervous system (CNS) caused by podosin mutations. [5],[6] Mutations of the podocin gene were shown to be responsible for up to 40% of all cases of NS occurring in the first 3 months of life. [7] Subsequent studies further defined the phenotype associated with mutations in the NPHS2 gene; patients who develop NS from birth to 6 months of age do not respond to immunosuppressive agents and reach end-stage renal disease (ESRD) before the end of the first decade of life. [8],[9],[10] Co-existence of NPHS1 and NPHS2 mutations has been reported in patients with CNS disease. [11],[12]

We report a child aged 4 months with steroidresistant NS (SRNS) who had polymorphism of NPHS1 (E117K) and mutation of NPHS2 (P118L).

   Case Report Top

An 18-month-old girl was admitted to the hospital with edema of her eyelids and decreased urine output. She had her first attack at the age of 4 months. She was born through a normal delivery with a birth weight of 3000 g and had no significant problem at birth. Neuromotor development was suitable for her age. She began to walk at the age of 13 months and talk a few words at the age of 10 months. She had three healthy siblings, all older than her. There was no history of renal disease in any of the relatives; her parents were not consanguineous. On physical examination, she was found to have good interaction with her mother and was well oriented with her environment. The body weight was in 10 th - 25 th percentile and height was in 50 th - 75 th percentile. Her vital findings and blood pressure values were within normal ranges, and systemic examination was normal except for tiny hair and dental caries. Laboratory evaluation showed normochromic normocytic anemia, with high erythrocyte sedimentation rate (140 mm/h). The other findings were: total protein 4.3 g/dL, albumin 2.0 g/dL, serum urea 101 mg/dL, creatinine 0.8 mg/dL, uric acid 8 mg/dL, and phosphorus 9.6 mg/dL. She also had hyperlipidemia. Estimated glomerular filtration rate (GFR) (with modified Schwartz) was 41.3 mL/min per 1.73 m 2 , appropriate with stage-2 chronic kidney disease (CKD). Serum complement levels were normal, viral serological markers were negative, and there was no bone developmental delay. Thyroid and parathyroid function tests were in the normal range. Urinary osmolality was 274-300 mOsm, urine protein/creatinine ratio was 20 mg, and urine electrophoresis showed glomerular proteinuria. Urine sediment and culture were normal. Renal ultrasonography showed bilateral normal-sized kidneys with increased echogenicity. There were no cardiological anomalies, although she had features of volume overload. The patient was treated with intravenous diuretics and oral ramipril and candesartan. Considering her hypo-osmolar urine, kidneys with increased echogenicity and low GFR values, she was evaluated as stage-2 CKD and the supplementary treatment was given. The child was evaluated for detection of presence of any scar as well as the percentage of function of each kidney by isotope renal scanning. The Dimercapto succinic acid scan revealed that there was increased background activity of both kidneys, supporting the observation that she had bilateral renal dysfunction. Renal biopsy was performed and light microscopic evaluation of the renal biopsy specimen showed 35 glomeruli. Five of them were sclerotic and there was a segmental increase in podocytes and glomerular segmental adherence. In the other glomeruli, an increase of mesangial matrix and cellular structures was detected. In the interstitium, near the sclerotic glomeruli, fibrosis, atrophy, and cellular infiltration were present. There were also vacuolar changes in the tubulo-epithelial cells. The sample for immunofluorescense examination contained five glomeruli; none of them showed any immune deposits.

The child was treated with oral prednisolone (60 mg/m 2 /d) for 4 weeks; despite the treatment, proteinuria persisted. Subsequently, cyclosporine was added to her treatment. Analysis was performed for both podosin and nephrin mutation. E117K heterozygote mutation, interpreted as a polymorphism, was found in the nephrin gene (NPHS1) and mutation of P118L homozygote podosin gene (NPHS2) was found in the second exon [Figure 1].
Figure 1: The site of the P118L mutation in the second exon in podocin.

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   Discussion Top

We report a case of SRNS, carrying nephrin polymorphism and podosin mutation. The patient's nephrin gene mutation was evaluated due to the early onset of the NS. Nephrin mutation of E117K was determined as polymorphism. This has been frequently found in the normal population as a DNA sequence variation. Also, studies dealing with nephrin mutation have reported this amino acid change as polymorphism, instead of a disease-causing mutation.

Previous studies support that P118L mutation in NPHS2 carries a poor prognosis. It is located in the membrane domain of podocin and leads to an amino acid change with alteration of the podocin structure by affecting proteins of the stomatin family. [13] Nephrin and podocin, the protein products of the NPHS1 and NPHS2 genes, have important roles in the organization of the SD and interact via protein-protein pathway which maintains the function of the glomerular podocyte foot process. [7],[14],[15] After full embryological differentiation has occurred, nephrin is exclusively expressed in the podocytes at the level of the SD. [9] Nephrin strands contribute to the porous structure of the SD, forming pores responsible for size selectivity of SD and the glomerular filtration barrier (GFB). [10] In addition to this, nephrin has a role in intracellular signaling pathway maturation and the functional integrity of the podocyte. [16],[17] The presence of mutations in both NPHS1 and NPHS2 genes alter the podocyte structure and function. [18] Diseases causing podocin mutations alter the nephrin-induced signal transduction. [17] Caridi et al reported one patient with mutations in both genes in their study. [19] Schultheiss et al showed that 5 of 62 (8.06%) NPHS2 mutated patients also had NPHS1 mutation. [12] On the contrary, 11 of 12 (91%) NPHS2 mutation-negative patients had NPHS1 mutation. Four of five patients having both mutations also had R229Q(h) mutation, which belongs to NPHS2. The last patient was having V165X, E237Q(H) mutation besides the NPHS1. They concluded that the phenotype of the four patients with R229Q mutation was not altered. But with the limiting number of patients, their data did not suggest that patients with combined mutations in NPHS1 and NPHS2 show any genotype/ phenotype correlation. There are few patients reported to be having P118L mutant allele up to now. Two of them are siblings reported by Ozer et al. [20] They were 8 and 17 months of age, respectively, with the former being reported to be well without ESRD at 3 years of age, while the latter case died at 3 years due to pneumonia. NPHS1 mutational analysis was not done on them. In our study consisting of 592 cases with SRNS, we found a podocin mutation rate of 18%, and among these patients, P118L frequency was detected in 6 patients (5.6%) (unpublished data). Two of these six patients progressed to ESRD during follow-up. Recent studies reported varying clinical features resulting from different NPHS1 mutations. However, data on patients having combined NPHS1 and NPHS2 mutations are not available to make any comments on the phenotype. [12] The patient in this report was carrying polymorphic NPHS1 mutation and she also had NPHS2 mutation which phenotypically carries a poor prognosis. It may be questioned whether this polymorphic change (E117K) alters the signaling pathways of the podocyte and leads to P118L mutation. Thus, it should perhaps be called a genetic modifier in future.

   References Top

1.Huber TB, Hartleben B, Kim J, et al. Nephrin and CD2AP associate with phosphoinositide 3-OH kinase and stimulate AKT-dependent signaling. Mol Cell Biol 2003;23:4917-28.  Back to cited text no. 1
2.Jones N, Blasutig IM, Eremina V, et al. Nck adaptor proteins link nephrin to the actin cytoskeleton of kidney podocytes. Nature 2006; 440:818-23.  Back to cited text no. 2
3.Zhu J, Sun N, Aoudjit L, et al. Nephrin mediates actin reorganization via phosphoinositide 3-kinase in podocytes. Kidney Int 2008;73:556-66.  Back to cited text no. 3
4.Niaudet P, Boyer O. Idiopathic Nephrotic Syndrome in Children: Clinical Aspects. In Pediatric Nephrology 6 th ed. Avner ED, Harmon ED, Niaudet P, Yoshikawa N, eds. Berlin, Heidelberg: Springer-Verlag; 2009. p. 667-702  Back to cited text no. 4
5.Benzing T. Signaling at the slit diaphragm. J Am Soc Nephrol 2004;15:1382-91.  Back to cited text no. 5
6.Lehtonen S. Connecting the interpodocyte slit diaphragm and actindynamics: Emerging role for the nephrin signaling complex. Kidney Int 2008;73:903-5.  Back to cited text no. 6
7.Gbadegesin R, Smoyer WE. Nephrotic Syndrome. In Comprehensive Pediatric Nephrology. 1 st ed. In: Geary DF, Schaefer F, eds. Philadelphia: Mosby Elsevier; 2009. p. 205-18.  Back to cited text no. 7
8.Hinkes B, Vlangos C, Heeringa S, et al; APN Study Group. Specific podocin mutations Correlate with age of onset in steroid-resistant nephrotic syndrome. J Am Soc Nephrol 2008;19:365-71.  Back to cited text no. 8
9.Ruf RG, Lichtenberger A, Karle SM, et al; Arbeitsgemeinschaft Für Pädiatrische Nephrologie Study Group. Patients with mutations in NPHS2 (podocin) do not respond to standard steroid treatment of nephrotic syndrome. J Am Soc Nephrol 2004;15:722-32.  Back to cited text no. 9
10.Weber S, Gribouval O, Esquivel EL, et al. NPHS2 mutation analysis shows genetic heterogeneity of steroid-resistant nephrotic syndrome and low post-transplant recurrence. Kidney Int 2004;66:571-9.  Back to cited text no. 10
11.Koziell A, Grech V, Hussain S, et al. Geno-type/phenotype correlations of NPHS1 and NPHS2 mutations in nephrotic syndrome advocate a functional inter-relationship in glomerular filtration. Hum Mol Genet 2002;11:379-88.  Back to cited text no. 11
12.Schultheiss M, Ruf GR, Mucha EB, et al. No evidence for genotype/phenotype correlation in NPHS1 and NPHS2 mutations. Pediatr Nephrol 2004;19:1340-8.  Back to cited text no. 12
13.Roselli S, Moutkine I, Gribouval O, Benmerah A, Antignac C. Plasma membrane targeting of podocin through the classical exocytic pathway: Effect of NPHS2 mutations. Traffic 2004;5:37-44.  Back to cited text no. 13
14.Huber TB, Kottgen M, Schilling B, Walz G, Benzing T. Interaction with podocin facilitates nephrin signaling. J Biol Chem 2001;276:41543-6.  Back to cited text no. 14
15.Schwarz K, Simons M, Reiser J, et al. Podocine, a raft- associated component of the glomerular slit diaphragm, interacts with CD2AP and nephrin. J Clin Invest 2001;108:1583-7.  Back to cited text no. 15
16.Kaplan JM, Kim SH, North KN, et al. Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis. Nat Genet 2000;24:251-6.  Back to cited text no. 16
17.Ruf RG, Schultheiss M, Lichtenberger A, et al; APN Study Group. Prevalence of WT1 mutations in a large cohort of patients with steroid-resistant and steroid-sensitive nephrotic syndrome. Kidney Int 2004;66:564-70.  Back to cited text no. 17
18.Huber TB, Simons M, Hartleben B, et al. Molecular basis of the functional podocin -nephrin complex: Mutations in the NPHS2 gene disrupt nephrin targeting to lipid raft microdomains. Hum Mol Genet 2003;12:3397-405.  Back to cited text no. 18
19.Caridi G, Bertelli R, Di Duca M, et al. Broadening the spectrum of diseases related to podocin mutations. J Am Soc Nephrol 2003;14: 1278-86.  Back to cited text no. 19
20.Ozer EA, Aksu N, Erdoðan H, et al. A novel NPHS2 gene mutation in Turkish children with familial steroid-resistant nephrotic syndrome. Nephrology 2004;9:310-2.  Back to cited text no. 20

Correspondence Address:
Nida Dincel
Department of Pediatric Nephrology, Ege University Faculty of Medicine, Bornova, 35100 Izmir
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DOI: 10.4103/1319-2442.121300

PMID: 24231487

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