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01-12-2004 | Editorial Commentary

Genetic forms of nephrotic syndrome

Author: Patrick Niaudet

Published in: Pediatric Nephrology | Issue 12/2004

Abstract.

Mutations of NPHS1, NPHS2 , or WT1 may be responsible for severe forms of nephrotic syndrome in children, progressing to end-stage renal failure. Recent studies have shown that congenital nephrotic syndrome may be secondary to mutations of one of these three genes and that some patients have a digenic inheritance of NPHS1 and NPHS2 mutations. The clinical spectrum of NPHS2 mutations has broadened, with the demonstration that mutations in the respective gene podocin may be responsible for nephrotic syndrome occurring at birth, in childhood, or in adulthood. It is now well recognized that podocin mutations are found in 10%–30% of sporadic cases of steroid-resistant nephrotic syndrome with focal segmental glomerulosclerosis. Data from large cohorts indicate that the risk of recurrence of nephrotic syndrome after renal transplantation in patients with podocin mutations is very low.

Pollak M (2002) Inherited podocytopathies: FSGS and nephrotic syndrome from a genetic viewpoint. J Am Soc Nephrol 13:3016–3023PubMed

Antignac C (2002) Genetic models: clues for understanding the pathogenesis of idiopathic nephrotic syndrome. J Clin Invest 109:447–449CrossRefPubMed

Hallman N, Hjelt L, Ahvenainen EK (1956) Nephrotic syndrome in newborn and young infants. Ann Pediatr Fenn 2:227–241

Huttunen N-P (1976) Congenital nephrotic syndrome of Finnish type. Study of 75 cases. Arch Dis Child 51:344–348

Huttunen N-P, Rapola J, Vilska J, Hallman N (1980) Renal pathology in congenital nephrotic syndrome of Finnish type: a quantitative light microscopic study of 50 patients. Int J Pediatr Nephrol 1:10–16PubMed

Kestilä M, Lenkkeri U, 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 1:575–582CrossRefPubMed

Lenkkeri U, Männikkö M, McCready P, Lamerdin J, Gribouval O, Niaudet P, 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 64:51–61CrossRefPubMed

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

Fuchshuber A, Niaudet P, Gribouval O, Jean G, Gubler MC, Broyer M, Antignac C (1996) Congenital nephrotic syndrome of the Finnish type: linkage to the locus in a non-Finnish population. Pediatr Nephrol 10:135–138CrossRefPubMed

10.

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

11.

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 11:379–388CrossRefPubMed

12.

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 (in press)

13.

Patrakka J, Kestila M, Wartiovaara J, Ruotsalainen V, Tissari P, Lenkkeri U, Mannikko M, Visapaa I, Holmberg C, Rapola J, Tryggvason K, Jalanko H (2000) Congenital nephrotic syndrome (NPHS1); features resulting from different mutations in Finnish patients. Kidney Int 58:972–980CrossRefPubMed

14.

Fuchshuber A, Jean G, Gribouval O, Gubler MC, Broyer M, Beckmann JS, Niaudet P, Antignac C (1995) Mapping a gene ( SNR1) to chromosome 1q25-q31 in idiopathic nephrotic syndrome confirms a distinct entity of autosomal recessive nephrosis. Hum Mol Genet 4:2155–2158PubMed

15.

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 24:349–354CrossRefPubMed

16.

Roselli S, Gribouval O, Boute N, Sich M, Benessy F, Attie T, Gubler MC, Antignac C (2002) Podocin localizes in the kidney to the slit diaphragm area. Am J Pathol 160:131–139PubMed

17.

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 12:3397–3405CrossRefPubMed

18.

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 108:1621–1629CrossRefPubMed

19.

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 14:1278–1286PubMed

20.

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, Hildebrandt 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

21.

Weber S, Gribouval O, Esquivel EL, Morinière V, Tête 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 66:571–579CrossRefPubMed

22.

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

23.

Tsukaguchi H, Sudhakar A, Cam Le T, 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 110:1659–1666CrossRefPubMed

24.

Roselli S, Moutkine I, Gribouval O, Benmerah A, Antignac C (2003) Plasma membrane targeting of podocin through classical exocytic pathway: effect of NPHS2 mutations. Traffic 5:1–8

25.

Pereira AC, Pereira AB, Mota GF, Cunha RS, Herkenhoff FL, Pollak MR, Mill JG, Krieger JE (2004) NPHS2 R229Q functional variant is associated with microalbuminuria in the general population. Kidney Int 65:1026–1030CrossRefPubMed

26.

Karle SM, Uetz B, Ronner V, Glaeser L, Hildebrandt F, Fuchshuber A (2002) Novel mutations in NPHS2 detected in both familial and sporadic steroid-resistant nephrotic syndrome. J Am Soc Nephrol 13:388–393PubMed

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 13:400–405PubMed

28.

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 12:2742–2746PubMed

29.

Reddy JC, Licht JD (1996) The WT1 Wilms’ tumor suppressor gene: how much do we really know? Biochim Biophys Acta 1287:1–28CrossRefPubMed

30.

Pritchard-Jones K, Fleming S, Davidson D, Bickmore W, Porteous D, Gosden C, Bard J, Buckler A, Pelletier J, Housman D (1990) The candidate Wilms’ tumour gene is involved in genitourinary development. Nature 346:194–197CrossRefPubMed

31.

Habib R, Loirat C, Gubler MC, Niaudet P, Bensman A, Levy M, Broyer M (1985) The nephropathy associated with male pseudohermaphroditism and Wilms’ tumor (Drash syndrome): a distinctive glomerular lesion, report of 10 cases. Clin Nephrol 24:269–278PubMed

32.

Little M, Wells C (1997) A clinical overview of WT1 gene mutations. Hum Mutat 9:209–225CrossRef

33.

Pelletier J, Bruening W, Kashtan CE, Mauer SM, Manivel JC, Striegel JE, Houghton DC, Junien C, Habib R, Fouser L (1991) Germline mutations in the Wilms’ tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome. Cell 67:437–447CrossRefPubMed

34.

Jeanpierre C, Béroud C, Niaudet P, Junien C (1998) Software and database for the analysis of mutations in the human WT1 gene. Nucleic Acids Res 26:273–277CrossRef

35.

Jeanpierre C, Denamur E, Cabanis MO, Luce 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 (IDMS) and analysis of genotype-phenotype correlations using a computerized mutation database. Am J Hum Genet 62:824–833CrossRefPubMed

36.

Yang Y, Jeanpierre C, Dressler GR, Lacoste M, Niaudet P, Gubler MC (1999) WT1 and PAX-2 podocyte expression in Denys-Drash syndrome and isolated diffuse mesangial sclerosis. Am J Pathol 154:181–192PubMed

37.

Dressler GR, Wilkinson JE, Rothenpieler UW, Patterson LT, Williams-Simons L, Westphal H (1993) Deregulation of Pax-2 expression in transgenic mice generates severe kidney abnormalities. Nature 362:65–67CrossRefPubMed

38.

Frasier S, Bashore RA, Mosier HD (1964) Gonadoblastoma associated with pure gonadal dysgenesis in monozygotic twins. J Pediatr 64:740–745PubMed

39.

Moorthy AV, Chesney RW, Lubinsky M (1987) Chronic renal failure and XY gonadal dysgenesis: “Frasier” syndrome—a commentary on reported cases. Am J Med Genet [Suppl 3]:297–302

40.

Barbaux S, Niaudet P, Gubler MC, Grunfeld JP, Jaubert F, Kuttenn F, Fekete CN, Souleyreau-Therville N, Thibaud E, Fellous M, McElreavey K (1997) Donor splice site mutations in the WT1 gene are responsible for Frasier syndrome. Nat Genet 17:467–469PubMed

41.

Kikuchi H, Takata A, Akasaka Y, Fukuzawa R, Yoneyama H, Kurosawa Y, Honda M, Kamiyama Y, Hata J (1998) Do intronic mutations affecting splicing of WT1 exon 9 cause Frasier syndrome ? J Med Genet 35:45–48PubMed

42.

Klamt B, Koziell A, Poulat F, Wieacker P, Scambler P, Berta P, Gessler M (1998) Frasier syndrome is caused by defective alternative splicing of WT1 leading to an altered ratio of WT1+/-KTS splice isoforms. Hum Mol Genet 7:709–714CrossRefPubMed

43.

Denamur E, Bocquet N, Mougenot B, Da Silva F, Martinat L, Loirat C, Elion J, Bensman A, Ronco PM (1999) Mother-to-child transmitted WT1 splice-site mutation is responsible for distinct glomerular diseases. J Am Soc Nephrol 10:2219–2223PubMed

44.

Demmer L, Primack W, Loik V, Brown R, Therville N, McElreavey K (1999) Frasier syndrome: a cause of focal segmental glomerulosclerosis in a 46,XX female. J Am Soc Nephrol 10:2215–2218PubMed

45.

Patrakka J, Ruotsalainen V, Reponen P, Qvist E, Laine J, Holmberg C, Tryggvason K, Jalanko H (2002) Recurrence of nephrotic syndrome in kidney grafts of patients with congenital nephrotic syndrome of the Finnish type: role of nephrin. Transplantation 73:394–403CrossRefPubMed

46.

Flynn JT, Schulman SL, de Chadarevian JP, Dunn SP, Kaiser BA, Polinsky MS, Baluarte HJ (1992) Treatment of steroid-resistant post-transplant nephrotic syndrome with cyclophosphamide in a child with congenital nephrotic syndrome. Pediatr Nephrol 6:553–555PubMed

47.

Laine J, Jalanko H, Holthöfer H, Krogerus L, Rapola J, Willebrand E von, Lautenschlager I, Salmela K, Holmberg C (1993) Post-transplantation nephrosis in congenital nephrotic syndrome of the Finnish type. Kidney Int 44:867–874PubMed

48.

Barayan S, Al-Akash S, Malekzadeh M, Marik JL, Cohen AH, Ettenger RB, Yadin O (2001) Immediate post-transplant nephrosis in a patient with congenital nephrotic syndrome. Pediatr Nephrol 16:547–549CrossRefPubMed

49.

Bertelli R, Ginevri F, Caridi G, Dagnino M, Sandrini S, Di Duca M, Emma F, Sanna-Cherchi S, Scolari F, Neri TM, Murer L, Massella L, Basile G, Rizzoni G, Perfumo F, Ghiggeri GM (2003) Recurrence of focal segmental glomerulosclerosis after renal transplantation in patients with mutations of podocin. Am J Kidney Dis 41:1314–1321CrossRefPubMed

50.

Billing H, Muller D, Ruf R, Lichtenberger A, Hildebrandt F, August C, Querfeld U, Haffner D (2004) NPHS2 mutation associated with recurrence of proteinuria after transplantation. Pediatr Nephrol 19:561–564CrossRefPubMed

51.

Carraro M, Caridi G, Bruschi M, Artero M, Bertelli R, Zennaro C, Musante L, Candiano G, Perfumo F, Ghiggeri GM (2002) Serum glomerular permeability activity in patients with podocin mutations (NPHS2) and steroid-resistant nephrotic syndrome. J Am Soc Nephrol 13:1946–1952PubMed

Title: Genetic forms of nephrotic syndrome
Author: Patrick Niaudet
Publication date: 01-12-2004
Publisher: Springer-Verlag
Published in: Pediatric Nephrology / Issue 12/2004
Print ISSN: 0931-041X
Electronic ISSN: 1432-198X
DOI: https://doi.org/10.1007/s00467-004-1676-9

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Genetic forms of nephrotic syndrome

Abstract.

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