Abstract
WT1 mutations have been considered a rare cause of nephrotic syndrome but recent reports challenge this assumption. Exclusion of inherited forms is a basic point in any therapeutic strategy to nephrotic syndrome since they do not respond to drugs. We screened for WT1 mutations in 200 patients with nephrotic syndrome: 114 with steroid resistance (SRNS) and 86 with steroid dependence (SDNS) for whom other inherited forms of nephrotic syndrome (NPHS2, CD2AP) had been previously excluded. Three girls out of 32 of the group with steroid resistance under 18 years presented classical WT1 splice mutations (IVS9+5G>A, IVS9+4C>T) of Frasier syndrome. Another one presented a mutation coding for an amino acid change (D396N) at exon 9 that is typical of Denys-Drash syndrome. All presented resistance to drugs and developed end stage renal failure within 15 years. Two girls of the Frasier group presented a 46 XY karyotype with streak gonads while one was XX and had normal gonad morphology. In the two cases with IVS9+5G>A renal pathology was characterized by capillary wall thickening with deposition of IgG and C3 in one that was interpreted as a membrane pathology. Foam cells were diffuse in tubule-interstitial areas. In conclusion, WT1 splice mutations are not rare in females under 18 years with SRNS. This occurs in absence of a clear renal pathology picture and frequently in absence of phenotype change typical of Frasier syndrome. In adults and children with SDNS, screening analysis is of no clinical value. WT1 hot spot mutation analysis should be routinely done in children with SRNS; if the molecular screening anticipates any further therapeutic approach it may modify the long term therapeutic strategy.
Similar content being viewed by others
Abbreviations
- FSGS:
-
Focal segmental glomerulosclerosis
- FS:
-
Frasier syndrome
- DDS:
-
Denys-Drash syndrome
References
Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH, Jones C, Housman DE (1990) Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms′ tumor locus. Cell 60:509–520
Haber DA, Park S, Maheswaran S, Englert C, Re GG, Hazen-Martin DJ, Sens DA, Garvin AJ (1993) WT1-mediated growth suppression of Wilms tumor cells expressing a WT1 splicing variant. Science 262:2057–2059
Gessler M, Konig A, Bruns GA (1992) The genomic organization and expression of the WT1 gene. Genomics 12:807–813
Hammes A, Guo JK, Lutsch G, Leheste JR, Landrock D, Ziegler U, Gubler MC, Schedl A (2001) Two splice variants of the Wilms′ tumor 1 gene have distinct functions during sex determination and nephron formation. Cell 106:319–329
Baird PN, Santos A, Groves N, Jadresic L, Cowell JK (1992) Constitutional mutations in the WT1 gene in patients with Denys-Drash syndrome. Hum Mol Genet 1:301–305
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 WT1 are responsible for Frasier syndrome. Nat Genet 17:467–470
Varanasi R, Bardeesy N, Ghahremani M, Petruzzi MJ, Nowak N, Adam MA, Grundy P, Shows TB, Pelletier J (1994) Fine structure analysis of the WT1 gene in sporadic Wilms tumors. Proc Natl Acad Sci USA 91:3554–3558
Kohsaka T, Tagawa M, Takekoshi Y, Yanagisawa H, Tadokoro K, Yamada M (1999) Exon 9 mutations in the WT1 gene, without influencing KTS splice isoforms, are also responsible for Frasier syndrome. Hum Mutat 14:466–470
Jeanpierre C, Denamur E, Henry I, 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, and analysis of genotype/phenotype correlations by use of a computerized mutation database. Am J Hum Genet 62:824–833
Ito S, Hataya H, Ikeda M, Takata A, Kikuchi H, Hata J, Morikawa Y, Kawamura S, Honda M (2003) Alport syndrome-like basement membrane changes in Frasier syndrome: an electron microscopy study. Am J Kidney Dis 41:1110–1115
Ruf RG, Schultheiss M, Lichtenberger A, Karle SM, Zalewski I, Mucha B, Everding AS, Neuhaus T, Patzer L, Plank C, Haas JP, Ozaltin F, Imm A, Fuchshuber A, Bakkaloglu A, Hildebrandt F (2004) Prevalence of WT1 mutations in a large cohort of patients with steroid-resistant and steroid-sensitive nephrotic syndrome. Kidney Int 66:564–570
Mucha B, Ozaltin F, Hinkes BG, Hasselbacher K, Ruf RG, Schultheiss M, Hangan D, Hoskins BE, Everding AS, Bogdanovic R, Seeman T, Hoppe B, Hildebrandt F (2006) Mutations in the Wilms′ tumor 1 gene cause isolated steroid resistant nephrotic syndrome and occur in exons 8 and 9. Pediatr Res 59:325–331
ISKDC (1974) Prospective, controlled trial of cyclophosphamide therapy in children with nephrotic syndrome. Report of the international study of kidney disease in children. Lancet 2:423–427
ISKDC (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
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
Caridi G, Perfumo F, Ghiggeri GM (2005) NPHS2 (Podocin) mutations in nephrotic syndrome. Clinical spectrum and fine mechanisms. Pediatr Res 57:54R–61R
Ghiggeri GM, Catarsi P, Scolari F, Caridi G, Bertelli R, Carrea A, Sanna-Cherchi S, Emma F, Allegri L, Cancarini G, Rizzoni GF, Perfumo F (2004) Cyclosporine in patients with steroid-resistant nephrotic syndrome: an open-label, nonrandomized, retrospective study. Clin Ther 26:1411–1418
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 7:709–714
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 10:2219–2223
Tsuda M, Owada M, Tsuchiya M, Murakami M, Sakiyama T (1999) WT1 nephropathy in a girl with normal karyotype (46,XX). Clin Nephrol 51:62–63
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 10:2215–2218
Loirat C, Andre JL, Champigneulle J, Acquaviva C, Chantereau D, Bourquard R, Elion J, Denamur E (2003) WT1 splice site mutation in a 46,XX female with minimal-change nephrotic syndrome and Wilms′ tumour. Nephrol Dial Transplant 18:823–825
Acknowledgements
This work was completed with the financial support of the Italian Ministry of Health and Fondazione Mara, Wilma e Bianca Querci (Project:‘’Nuove evoluzioni sulla multifattorialità della sindrome nefrosica’’).
Author information
Authors and Affiliations
Corresponding author
Additional information
Filippo Aucella and Luigi Bisceglia contributed equally to the work.
Rights and permissions
About this article
Cite this article
Aucella, F., Bisceglia, L., De Bonis, P. et al. WT1 mutations in nephrotic syndrome revisited. High prevalence in young girls, associations and renal phenotypes. Pediatr Nephrol 21, 1393–1398 (2006). https://doi.org/10.1007/s00467-006-0225-0
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00467-006-0225-0