Skip to main content
SpringerLink
Log in

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

  • Original Article
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Arbeitsgemeinschaft fur Pädiatrische Nephrologie (1988) Short versus standard prednisone therapy for initial treatment of idiopathic nephrotic syndrome in children. Lancet 1:380–383

    Google Scholar 

  2. International Study of Kidney Disease in Children (1981) Primary nephrotic syndrome in children: clinical significance of histopathologic variants of minimal change and of diffuse mesangial hypercellularity. A report of the International Study of Kidney Disease in Children. Kidney Int 20:765–771

    Article  Google Scholar 

  3. Fuchshuber A, Jean G, Gribouval O, Gubler MC, Broyer M, Beckmann JS, Niaudet P, Antignac C (1995) Mapping a gene (SRN1) to chromosome 1q25-q31 in idiopathic nephrotic syndrome confirms a distinct entity of autosomal recessive nephrosis. Hum Mol Genet 4:2155–2158

    Article  CAS  Google Scholar 

  4. Fuchshuber A, Gribouval O, Ronner V, Kroiss S, Karle S, Brandis M, Hildebrandt F (2001) Clinical and genetic evaluation of familial steroid-responsive nephrotic syndrome in childhood. J Am Soc Nephrol 12:374–378

    CAS  PubMed  Google Scholar 

  5. Kestila M, Lenkkeri U, Mannikko M, Lamerdin J, McCready P, Putaala H, Ruotsalainen V, Morita T, Nissinen M, Herva R, Kashtan CE, Peltonen L, Holmberg C, Olsen A, Tryggvason K (1998) Positionally cloned gene for a novel glomerular protein—nephrin—is mutated in congenital nephrotic syndrome. Mol Cell 4:575–582

    Article  Google Scholar 

  6. Winn MP, Conlon PJ, Lynn KL, Howell DN, Slotterbeck BD, Smith AH, Graham FL, Bembe M, Quarles LD, Pericak-Vance MA, Vance JM (1999) Linkage of a gene causing familial focal segmental glomerulosclerosis to chromosome 11 and further evidence of genetic heterogeneity. Genomics 58:113–120

    Article  CAS  Google Scholar 

  7. Kaplan JM, Kim SH, North KN, Rennke H, Correia LA, Tong HQ, Mathis BJ, Rodriguez-Perez JC, Allen PG, Beggs AH, Pollak MR (2000) Mutations in ACTN4, encoding α-actinin-4, cause familial focal segmental glomerulosclerosis. Nat Genet 24:251–256

    Article  CAS  Google Scholar 

  8. Boute N, Gribouval O, Roselli S, Benessy F, Lee H, Fuchshuber A, Dahan K, Gubler MC, Niaudet P, Antignac C (2000) NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome. Nat Genet 24:349–354

    Article  CAS  Google Scholar 

  9. Roselli S, Gribouval O, Boute N, Sich M, Benessy F, Attie T, Gubler MC, Antignac C (2001) Podocin localizes in the kidney to the slit diaphragm area. Am J Pathol 160:131–139

    Article  Google Scholar 

  10. Huber TB, Simons M, Hartleben B, Sernetz L, Schmidts M, Gundlech E, Saleem MA, Walz G, Benzing T (2003) Molecular basis of the functional podocin-nephrin complex: mutations in the NPHS2 gene disrupt nephrin targeting to the lipid raft microdomains. Hum Mol Genet 12:3397–3405

    Article  CAS  Google Scholar 

  11. Schwarz K, Simons M, Reiser J, Saleem MA, Faul C, Kriz W, Shaw AS, Holzman LB, Mundel P (2001) Podocin, a raft-associated component of the glomerular slit diaphragm, interacts with CD2AP and nephrin. J Clin Invest 108:1621–1629

    Article  CAS  Google Scholar 

  12. Caridi G, Berdeli A, Dagnino M, DiLuca M, Mir S, Cura A, Ravazzolo R, Ghiggeri GM (2004) Infantile steroid-resistant nephrotic syndrome associated with double homozygote mutations of podocin. Am J Kidney Dis 43:727–732

    Article  Google Scholar 

  13. Caridi G, Bertelli R, Carrea A, Di Duca M, Catarsi P, Artero M, Carraro M, Zennaro C, Candiano G, Musante L, Seri M, Ginevri F, Perfumo F, Ghiggeri GM (2001) Prevalence, genetics, and clinical features of patients carrying podocin mutations in steroid-resistant nonfamilial focal segmental glomerulosclerosis. J Am Soc Nephrol 12:2742–2746

    CAS  PubMed  Google Scholar 

  14. Caridi G, Bertelli R, Di Duca M, Dagnino M, Emma F, Onetti Muda A, Scolari F, Miglietti N, Mazzucco G, Murer L, Carrea A, Massella L, Rizzoni G, Perfumo F, Ghiggeri GM (2003) Broadening the spectrum of diseases related to podocin mutations. J Am Soc Nephrol 14:1278–1286

    Article  CAS  Google Scholar 

  15. Caridi G, Bertelli R, Scolari F, Sanna-Cherchi S, Di Duca M, Ghiggeri GM (2003) Podocin mutations in sporadic focal-segmental glomerulosclerosis occurring in adulthood. Kidney Int 64:365

    Article  CAS  Google Scholar 

  16. Caridi G, Perfumo F, Ghiggeri GM (2005) NPHS2 (podocin) mutations in nephrotic syndrome. Clinical spectrum and fine mechanisms. Pediatr Res 57:54–61

    Article  Google Scholar 

  17. Ruf RG, Lichtenberger A, Karle SM, Haas JP, Anacleto FE, Schultheiss M, Zalewski I, Imm A, Ruf EM, Mucha B, Bagga A, Neuhaus T, Fuchshuber A, Bakkaloglu A, Hildebrant F (2004) Patients with mutations in NPHS2 (podocin) do not respond to standard steroid treatment of nephrotic syndrome. J Am Soc Nephrol 15:722–732

    Article  Google Scholar 

  18. Weber S, Gribouval O, Esquivel EL, Moriniere V, Tete MJ, Legendre C, Niaudet P, Antignac C (2004) NPHS2 mutation analysis shows genetic heterogeneity of steroid-resistant nephrotic syndrome and low post-transplant recurrence. Kidney Int 66:571–579

    Article  CAS  Google Scholar 

  19. Ozer EA, Aksu N, Erdogan H, Yavascan O, Kara O, Gribouval O, Gubler MC, Antignac C (2004) A novel NPHS2 gene mutation in Turkish children with familial steroid-resistant nephrotic syndrome. Nephrology 9:310–312

    Article  CAS  Google Scholar 

  20. Ozcakar ZB, Cengiz FB, Cakar N, Uncu N, Kara N, Acar B, Yuksel S, Ekim M, Tekin M, Yalcinkaya F (2006) Analysis of NPHS2 mutations in Turkish steroid-resistant nephrotic syndrome patients. Pediatr Nephrol 21:1093–1096

    Article  Google Scholar 

  21. D’Agati VD, Fogo AB, Bruijn JA, Jennette JC (2004) Pathologic classification of focal segmental glomerulosclerosis: a working proposal. Am J Kidney Dis 43:368–382

    Article  Google Scholar 

  22. Karle S, Uetz B, Ronner V, Glaeser L, Hildebrandt F, Fuchshuber A, Members of the APN Study Group (2002) Novel mutations in NPHS2 are detected in familial and sporadic steroid-resistant nephrotic syndrome. J Am Soc Nephrol 13:388–393

    CAS  PubMed  Google Scholar 

  23. Kitamura A, Tsukaguchi H, Iijima K, Araki J, Hattori M, Ikeda M, Honda M, Nozu K, Nakazato H, Yoshikawa N, Kagami S, Muramatsu M, Choi Y, Cheong HI, Doi T (2006) Genetics and clinical features of 15 Asian families with steroid-resistant nephrotic syndrome. Nephrol Dial Transplant 21:3133–3138

    Article  CAS  Google Scholar 

  24. Yu Z, Ding J, Huang J, Yao Y, Xiao H, Zhang J, Liu J, Yang J (2005) Mutations in NPHS2 in sporadic steroid-resistant nephrotic syndrome in Chinese children. Nephrol Dial Transplant 20:902–908

    Article  CAS  Google Scholar 

  25. Lenkkeri U, Mannikko M, McCready P, Lamerdin J, Gribouval O, Niaudet PM, Antignac CK, Kashtan CE, Homberg C, Olsen A, Kestila M, Tryggvason K (1999) Structure of the gene for congenital nephrotic syndrome of the Finnish type (NPHS1) and characterization of mutations. Am J Hum Genet 64:51–61

    Article  CAS  Google Scholar 

  26. Dusel JA, Burdon KP, Hicks PJ, Hawkins GA, Bowden DW, Freedman BI (2005) Identification of podocin (NPHS2) gene mutations in African Americans with nondiabetic end-stage renal disease. Kidney Int 68:256–262

    Article  CAS  Google Scholar 

  27. Frishberg Y, Rinat C, Megged O, Shapira E, Feinstein S, Raas-Rothschild A (2002) Mutations in NPHS2 encoding podocin are a prevalent cause of steroid-resistant nephrotic syndrome among Israeli-Arab children. J Am Soc Nephrol 3:400–405

    Google Scholar 

  28. Maruyama K, Iijima K, Ikeda M, Kitamura A, Tsukaguchi H, Yoshiya K, Hoshii S, Wada N, Uemura O, Satomura K, Honda M, Yoshikawa N (2003) NPHS2 mutations in sporadic steroid-resistant nephrotic syndrome in Japanese children. Pediatr Nephrol 18:412–416

    Article  Google Scholar 

  29. Tsukaguchi H, Sudhakar A, Le TC, Nguyen T, Yao J, Schwimmer JA, Schachter AD, Poch E, Abreu PF, Appel GB, Pereira AB, Kalluri R, Pollak MR (2002) NPHS2 mutations in late-onset focal segmental glomerulosclerosis: R229Q is a common disease associated allele. J Clin Invest 110:1659–1666

    Article  CAS  Google Scholar 

  30. Franceschini N, North KE, Kopp JB, McKenzie L, Winkler C (2006) NPHS2 gene, nephrotic syndrome and focal segmental glomerulosclerosis: a HuGE review. Genet Med 8:63–75

    Article  CAS  Google Scholar 

  31. Wu MC, Wu JY, Lee CC, Tsai CH, Tsai FJ (2001) A novel polymorphism (c288C>T) of the NPHS2 gene identified in a Taiwan Chinese family. Hum Mutat 17:81–82

    Article  CAS  Google Scholar 

  32. Schultheiss M, Ruf RG, Mucha BE, Wiggins R, Fuchshuber A, Lichtenberger A, Hildebrandt F (2004) No evidence for genotype/phenotype correlation in NPHS1 and NPHS2 mutations. Pediatr Nephrol 19:1340–1348

    Article  Google Scholar 

  33. Komatsuda A, Wakui H, Maki N, Kigawa A, Goto H, Ohtani H, Hamai K, Oyama Y, Makoto H, Sawada K, Imai H (2003) Analysis of mutations in alpha-actinin 4 and podocin genes of patients with chronic renal failure due to sporadic focal segmental glomerulosclerosis. Ren Fail 25:87–93

    Article  CAS  Google Scholar 

  34. Roselli S, Moutkine I, Gribouval O, Benmerah A, Antignac C (2004) Plasma membrane targeting of podocin through the classical exocytic pathway: effect of NPHS2 mutations. Traffic 5:1–8

    Article  Google Scholar 

  35. Niaudet P (2004) Podocin and nephrotic syndrome: implications for the clinician. J Am Soc Nephrol 15:832–834

    Article  Google Scholar 

  36. Koziell A, Grech V, Hussain S, Lee G, Lenkkeri U, Tryggvason K, Scambler P (2002) Genotype/phenotype correlations of NPHS1 and NPHS2 mutations in nephrotic syndrome advocate a functional interrelationship in glomerular filtration. Hum Mol Genet 11:379–388

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Molecular Genetics, Ege University Faculty of Medicine, Izmir, Turkey

    Afig Berdeli

  2. Pediatric Nephrology, Ege University Faculty of Medicine, Izmir, Turkey

    Sevgi Mir & Onder Yavascan

  3. Pediatric Nephrology, Behcet Uz Children’s Hospital, Izmir, Turkey

    Erkin Serdaroglu & Mustafa Bak

  4. Pediatric Nephrology, Tepecik Teaching and Research Hospital, Izmir, Turkey

    Nejat Aksu

  5. Pediatric Nephrology, Sami Ulus Children’s Hospital, Ankara, Turkey

    Ayse Oner

  6. Faculty of Medicine, Pediatric Nephrology, Cukurova University, Adana, Turkey

    Ali Anarat

  7. Pediatric Nephrology, Faculty of Medicine, Uludag University, Bursa, Turkey

    Osman Donmez

  8. Pediatric Nephrology, Goztepe Teaching and Research Hospital, Izmir, Turkey

    Nurhan Yildiz

  9. Pediatric Nephrology, Cerrahpasa Faculty of Medicine, Istanbul University, Istanbul, Turkey

    Lale Sever

  10. Pediatric Nephrology, Inonu University Faculty of Medicine, Malatya, Turkey

    Yilmaz Tabel

  11. Pediatric Nephrology, Erciyes University Faculty of Medicine, Kayseri, Turkey

    Ruhan Dusunsel

  12. Pediatric Nephrology, Aydin Adnan Menderes University Faculty of Medicine, Aydin, Turkey

    Ferah Sonmez

  13. Pediatric Nephrology, Ankara Diskapi Education and Research Hospital, Ankara, Turkey

    Nilgun Cakar

Authors
  1. Afig Berdeli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sevgi Mir
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Onder Yavascan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Erkin Serdaroglu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mustafa Bak
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nejat Aksu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ayse Oner
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ali Anarat
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Osman Donmez
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Nurhan Yildiz
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Lale Sever
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Yilmaz Tabel
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Ruhan Dusunsel
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Ferah Sonmez
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Nilgun Cakar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Afig Berdeli.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Berdeli, A., Mir, S., Yavascan, O. et al. NPHS2 (podicin) mutations in Turkish children with idiopathic nephrotic syndrome. Pediatr Nephrol 22, 2031–2040 (2007). https://doi.org/10.1007/s00467-007-0595-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-007-0595-y

Keywords

Search

Navigation