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Novel mutations in steroid-resistant nephrotic syndrome diagnosed in Tunisian children

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Abstract

Steroid-resistant nephrotic syndrome (NS) remains one of the most intractable causes of end-stage renal disease in the first two decades of life. Several genes have been involved including NPHS1, NPHS2, WT1, PLCE1, and LAMB2. Our aim was to identify causative mutations in these genes, in 24 children belonging to 13 families with NS manifesting with various ages of onset. We performed haplotype analysis and direct exon sequencing of NPHS1, NPHS2, PLCE1, LAMB2, and the relevant exons 8 and 9 of WT1. Ten different pathogenic mutations were detected in seven families concerning four genes (NPHS1 (3/7), LAMB2 (2/7), NPHS2 (1/7), and WT1 (1/7)). Five of the detected mutations were novel; IVS9 + 2 T > C and p.D616G in NPHS1; p.E371fsX16 in NPHS2, and p.E705X and p.D1151fsX23 in LAMB2. Nine of 24 patients failed to be categorized by mutational analysis. Our study extends the spectrum of abnormalities underlying NS, by reporting novel mutations in the NPHS1 and NPHS2 genes and the first cases of LAMB2 mutations in Tunisia. Congenital and infantile NS can be explained by mutations in NPHS1, NPHS2, WT1, or LAMB2 genes. The identification of additional genes mutated in NS can be anticipated.

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References

  1. A Report of the 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. Kidney Int 20:756–771

    Google Scholar 

  2. Korbet SM (1998) Primary focal segmental glomerulosclerosis. J Am Soc Nephrol 9:1333–1340

    CAS  PubMed  Google Scholar 

  3. Myllymäki J, Saha H, Mustonen J, Helin H, Pasternack A (2003) IgM nephropathy: clinical picture and long-term prognosis. Am J Kidney Dis 41:343–350

    Article  PubMed  Google Scholar 

  4. 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  PubMed  Google Scholar 

  5. 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 nephritic syndrome. Nat Genet 24:349–354

    Article  CAS  PubMed  Google Scholar 

  6. Machuca E, Benoit G, Antignac C (2009) Genetics of nephrotic syndrome: connecting molecular genetics to podocyte physiology. Hum Mol Genet 18:185–194

    Article  Google Scholar 

  7. Zenker M, Machuca E, Antignac C (2009) Genetics of nephrotic syndrome: new insights into molecules acting at the glomerular filtration barrier. J Mol Med 87:849–857

    Article  CAS  PubMed  Google Scholar 

  8. Miner JH (1999) Renal basement membrane component. Kidney Int 56:2016–2024

    Article  CAS  PubMed  Google Scholar 

  9. 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 1:575–582

    Article  CAS  PubMed  Google Scholar 

  10. 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 inter-relationship in glomerular filtration. Hum Mol Genet 11:379–388

    Article  CAS  PubMed  Google Scholar 

  11. 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  PubMed  Google Scholar 

  12. Wing MR, Bourdon DM, Harden TK (2003) PLC-epsilon: a shared effector protein in Ras-, Rho-, and G alpha beta gamma-mediated signaling. Mol Interv 3:273–280

    Article  CAS  PubMed  Google Scholar 

  13. Hinkes B, Wiggins RC, Gbadegesin R, Vlangos CN, Seelow D, Nurnberg G, Garg P, Verma R, Chaib H, Hoskins BE, Ashraf S, Becker C, Hennies HC, Goyal M, Wharram BL, Schachter AD, Mudumana S, Drummond I, Kerjaschki D, Waldherr R, Dietrich A, Ozaltin F, Bakkaloglu A, Cleper R, Basel-Vanagaite L, Pohl M, Griebel M, Tsygin AN, Soylu A, Muller D, Sorli CS, Bunney TD, Katan M, Liu J, Attanasio M, O’Toole JF, Hasselbacher K, Mucha B, Otto EA, Airik R, Kispert A, Kelley GG, Smrcka AV, Gudermann T, Holzman LB, Nurnberg P, Hildebrandt F (2006) Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible. Nat Genet 38:1397–1405

    Article  CAS  PubMed  Google Scholar 

  14. Shih NY, Li J, Karpitskii V, Nguyen A, Dustin ML, Kanagawa O, Miner JH, Shaw AS (1999) Congenital nephrotic syndrome in mice lacking CD2-associated protein. Science 286:312–315

    Article  CAS  PubMed  Google Scholar 

  15. Benoit G, Machuca E, Nevo F, Gribouval O, Lepage D, Antignac C (2010) Analysis of recessive CD2AP and ACTN4 mutations in steroid-resistant nephritic syndrome. Pediatr Nephrol 25:445–451

    Article  PubMed  Google Scholar 

  16. Pelletier J, Bruening W, Li FP, Haber DA, Housman DE (1991) WT1 mutations contribute to abnormal genital system development and hereditary Wilms’ tumour. Nature 353:431–434

    Article  CAS  PubMed  Google Scholar 

  17. Barbaux S, Niaudet P, Gubler MC, Grünfeld JP, Jaubert F, Kuttenn F, Fékété CN, Souleyreau-Therville N, Thibaud E, Fellous M, McElreavey K (1997) Donor splice-site mutations in WT1 are responsible for Frasier syndrome. Nat Genet 17:467–470

    Article  CAS  PubMed  Google Scholar 

  18. Pierson M, Cordier J, Hervouuet F, Rauber G (1963) An unusual congenital and familial congenital malformative combination involving the eye and kidney. J Génét Hum 12:184–213

    CAS  PubMed  Google Scholar 

  19. Matejas V, Hinkes B, Alkandari F, Al-Gazali L, Annexstad E, Aytac MB, Barrow M, Bláhová K, Bockenhauer D, Cheong HI, Maruniak-Chudek I, Cochat P, Dötsch J, Gajjar P, Hennekam RC, Janssen F, Kagan M, Kariminejad A, Kemper MJ, Koenig J, Kogan J, Kroes HY, Kuwertz-Bröking E, Lewanda AF, Medeira A, Muscheites J, Niaudet P, Pierson M, Saggar A, Seaver L, Suri M, Tsygin A, Wühl E, Zurowska A, Uebe S, Hildebrandt F, Antignac C, Zenker M (2010) Mutations in the human laminin beta2 (LAMB2) gene and the associated phenotypic spectrum. Hum Mutat 31:1–11

    Article  Google Scholar 

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

    Google Scholar 

  21. Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215

    Article  CAS  PubMed  Google Scholar 

  22. Ramensky V, Bork P, Sunyaev S (2002) Human non-synonymous SNPs: aerver and survey. Nucleic Acids Res 30:3894–3900

    Article  CAS  PubMed  Google Scholar 

  23. Sunyaev S, Ramensky V, Koch I, Lathe W III, Kondrashov AS, Bork P (2001) Prediction of deleterious human alleles. Hum Mol Genet 10:591–597

    Article  CAS  PubMed  Google Scholar 

  24. Brunak S, Engelbrecht J, Knudsen S (1991) Prediction of human mRNA donor and acceptor sites from the DNA sequence. J Mol Biol 220:49–65

    Article  CAS  PubMed  Google Scholar 

  25. Beltcheva O, Martin P, Lenkkeri U, Tryggvason K (2001) Mutation spectrum in the nephrin gene (NPHS1) in congenital nephrotic syndrome. Hum Mutat 17:368–373

    Article  CAS  PubMed  Google Scholar 

  26. Machuca E, Benoit G, Nevo F, Tête MJ, Gribouval O, Pawtowski A, Brandström P, Loirat C, Niaudet P, Gubler MC, Antignac C (2010) Genotype-phenotype correlations in non-Finnish congenital nephrotic syndrome. J Am Soc Nephrol 21:1209–1217

    Article  CAS  PubMed  Google Scholar 

  27. Choi HJ, Lee BH, Kang JH, Jeong HJ, Moon KC, Ha IS, Yu YS, Matejas V, Zenker M, Choi Y, Cheong HI (2008) Variable phenotype of Pierson syndrome. Pediatr Nephrol 23:995–1000

    Article  PubMed  Google Scholar 

  28. Jeanpierre C, Denaamur E, Cabanis MO, Lucce S, Cecille A, Elion J, Peuchmaur M, Loirat C, Niaudet P, Gubler MC, Junien C (1998) Identification of constitutional WT1 mutations in patients with isolated diffuse mesangial sclerosis and analysis of genotype-phenotype correlations using a computerized mutation database. Am J Hum Genet 62:824–833

    Article  CAS  PubMed  Google Scholar 

  29. Frishberg Y, Ben-Neriah Z, Suvanto M, Rinat C, Männikkö M, Feinstein S, Becker-Cohen R, Jalanko H, Zlotogora J, Kestilä M (2007) Misleading findings of homozygosity mapping resulting from three novel mutations in NPHS1 encoding nephrin in a highly inbred community. Genet Med 9:180–184

    Article  CAS  PubMed  Google Scholar 

  30. Bolk S, Puffenberger EG, Hudson J, Morton DH, Chakravarti A (1999) Elevated frequency and allelic heterogeneity of congenital nephrotic syndrome, Finnish type, in the old order Mennonites. Am J Hum Genet 65:1785–1790

    Article  CAS  PubMed  Google Scholar 

  31. Pannain S, Weiss RE, Jackson CE, Dian D, Beck JC, Sheffield VC, Cox N, Refetoff S (1999) Two different mutations in the thyroid peroxidase gene of a large inbred Amish kindred: power and limits of homozygosity mapping. J Clin Endocrinol Metab 84:1061–1071

    Article  CAS  PubMed  Google Scholar 

  32. Miano MG, Jacobson SG, Carothers A, Hanson I, Teague P, Lovell J, Cideciyan AV, Haider N, Stone EM, Sheffield VC, Wright AF (2000) Pitfalls in homozygosity mapping. Am J Hum Genet 67:1348–1351

    CAS  PubMed  Google Scholar 

  33. Caridi G, Trivelli A, Sanna-Cherchi S, Perfumo F, Ghiggeri GM (2010) Familial forms of nephrotic syndrome. Pediatr Nephrol 25:41–52

    Article  Google Scholar 

  34. Sako M, Nakanishi K, Obana M, Yata N, Hoshii S, Takahashi S, Wada N, Takahashi Y, Kaku Y, Satomura K, Ikeda M, Honda M, Iijima K, Yoshikawa N (2005) Analysis of NPHS1, NPHS2, ACTN4, and WT1 in Japanese patients with congenital nephrotic syndrome. Kidney Int 67:1248–1255

    Article  CAS  PubMed  Google Scholar 

  35. Gigante M, Monno F, Roberto R, Laforgia N, Assael MB, Livolti S, Caringella A, La Manna A, Masella L, Iolascon A (2002) Congenital nephritic syndrome of the Finnish type in Italy: a molecular approach. J Nephrol 15:696–702

    CAS  PubMed  Google Scholar 

  36. Hinkes B, Mucha B, Vlangos C, Gbadegesin R, Liu J, Hasselbachera K, Hangan D, Ozaltin F, Zenker M, Hildebrandt F, members of the Arbeitsgemeinschaft für Paediatrische Nephrologie Study Group (2007) Nephrotic syndrome in the first year of life: two thirds of cases are caused by mutations in 4 genes (NPHS1, NPHS2, WT1, and LAMB2). Pediatrics 119:907–919

    Article  Google Scholar 

  37. Philippe A, Nevo F, Esquivel EL, Reklaityte D, Gribouval O, Tete MJ, Loirat C, Dantal J, Fischbach M, Pouteil-Noble C, Decramer S, Hoehne M, Benzing T, Charbit M, Niaudet P, Antignac C (2008) Nephrin mutations can cause childhood-onset steroidresistant nephrotic syndrome. J Am Soc Nephrol 19:1871–1878

    Article  CAS  PubMed  Google Scholar 

  38. Jalanko H (2009) Congenital nephrotic syndrome. Pediatr Nephrol 24:2121–2128

    Article  PubMed  Google Scholar 

  39. Ismaili K, Pawtowski A, Boyer O, Wissing KM, Janssen F, Hall M (2009) Genetic forms of nephrotic syndrome: a single-center experience in Brussels. Pediatr Nephrol 24:287–294

    Article  PubMed  Google Scholar 

  40. Berdeli A, Mir S, Yavascan O, Serdaroglu E, Bak M, Aksu N, Oner A, Anarat A, Donmez O, Yildiz N, Sever L, Tabel Y, Dusunsel R, Sonmez F, Cakar N (2007) NPHS2 (podocin) mutations in Turkish children with idiopathic nephrotic syndrome. Pediatr Nephrol 22:2031–2040

    Article  PubMed  Google Scholar 

  41. Löwik MM, Groenen PJ, Levtchenko EN, Monnens LA, Van den Heuvel LP (2009) Molecular genetic analysis of podocyte genes in focal segmental glomerulosclerosis—a review. Eur J Pediatr 168:1291–1304

    Article  PubMed  Google Scholar 

  42. Chermin G, HeeringaSF GR, Liu J, Hinkes BG, Vlangos CN, Vega-Warner V, Hildebrandt F (2008) Low prevalence of NPHS2 mutations in African American children with steroid-resistant nephritic syndrome. Pediatr Nephrol 23:1455–1460

    Article  Google Scholar 

  43. Cho HY, Lee JH, Choi HJ, Lee BH, Ha IS, Choi Y, Cheong HI (2008) WT1 and NPHS2 mutations in Korean children with steroid-resistant nephrotic syndrome. Pediatr Nephrol 23:63–70

    Article  PubMed  Google Scholar 

  44. Little M, Holmes G, Bickmore W, Van Heyningen V, Hastie N, Wainwright B (1995) DNA binding capacity of the WT1 protein is abolished by Denys-Drash syndrome WT1 point mutations. Hum Mol Genet 4:351–358

    Article  CAS  PubMed  Google Scholar 

  45. McTaggart SJ, Algar E, Chow CW, Powell HR, Jones CL (2001) Clinical spectrum of Denys-Drash and Frasier syndrome. Pediatr Nephrol 16:335–339

    Article  CAS  PubMed  Google Scholar 

  46. Schumacher V, Schneider S, Figgz A, Wildhardt G, Harms D, Schmidt D, Weirich A, Ludwig R, Royer-Pokora B (1997) Correlations of germline mutations and two-hit inactivation of the WT1 gene with Wilms tumors of stromal-predominant histology. Proc Natl Acad Sci USA 94:3972–3977

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This study was funded by a grant for French–Tunisian cooperation from Inserm/DGRST and by the Tunisian Ministry of Higher Education and Scientific Research (UR 04/28 and 02/UR/08-12).

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Authors and Affiliations

  1. Biochemistry Department, Sahloul University Hospital, 4054, Sousse, Tunisia

    Ibtihel Benhaj Mbarek, Asma Omezzine & Ali Bouslama

  2. Pediatric Department, Sahloul University Hospital, Sousse, Tunisia

    Saoussen Abroug & Abdelaziz Harbi

  3. Assistance Publique-Hôpitaux de Paris (AP-HP), Département de Génétique, Hôpital Necker-Enfants Malades, Paris, France

    Audrey Pawtowski, Marie Claire Gubler & Corinne Antignac

  4. Inserm, U983, Hôpital Necker-Enfants Malades, Paris, France

    Marie Claire Gubler & Corinne Antignac

  5. Université Paris Descartes, Faculté de Médecine Paris Descartes, Paris, France

    Marie Claire Gubler & Corinne Antignac

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  1. Ibtihel Benhaj Mbarek
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  2. Saoussen Abroug
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  3. Asma Omezzine
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Correspondence to Asma Omezzine.

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Mbarek, I.B., Abroug, S., Omezzine, A. et al. Novel mutations in steroid-resistant nephrotic syndrome diagnosed in Tunisian children. Pediatr Nephrol 26, 241–249 (2011). https://doi.org/10.1007/s00467-010-1694-8

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