Mutations in the Wilms’ tumor suppressor gene 1 (WT1), most commonly within exons 8 or 9 or intron 9, are found in cases with the overlapping conditions of Denys–Drash and Frasier syndromes, as well as in patients with steroid-resistant nephrotic syndrome (SRNS). This study investigated the presence of WT1 gene mutations in cases with childhood SRNS, along with an evaluation of their clinical outcome. Twenty-seven Greek children with sporadic (19 cases) and familial (8 cases) SRNS were tested. Four phenotypically female patients with sporadic SRNS were found to carry de novo WT1 mutations, including two cases with p.R394W, and one case each with p.R366H, or n.1228+5G>A. Karyotype analysis found 46XX in three cases, but 46XY in one. No phenotype–genotype correlations were apparent in the WT1 gene positive cases since their clinical presentation varied broadly. Interestingly, one patient with a pathological WT1 nucleotide variation responded fully to combined therapy with cyclosporine A and corticosteroids. This study further illustrates that investigation of WT1 gene mutations is clinically useful to support definitive diagnosis in children presenting with SRNS in order to direct the most appropriate clinical management.
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Aucella F, Bisceglia L, De Bonis P (2006) WT1 mutations in nephrotic syndrome revisited. High prevalence in young girls, associations and renal phenotypes. Pediatr Nephrol 21:1393–1398
Barbaux S, Niaudet P, Gubler MC et al (1997) Donor splice-site mutations in WT1 are responsible for Frasier syndrome. Nat Genet 17:467–470
Barbosa AS, Hadjiathanasiou CG, Theodoridis C et al (1999) The same mutation affecting the splicing of WT1 gene is present on Frasier syndrome patients with or without Wilms’ tumor. Hum Mutat 13:146–153
Borel F, Barilla CK, Hamilton TB et al (1996) Effects of Denys−Drash syndrome point mutations on the DNA binding activity of the Wilms' tumor suppressor protein WT1. Biochemistry 35(37):12070–12076
Boute N, Gribouval O, Roselli S et al (2000) NPHS2, encoding the glomerular protein podocin, is mutated in autosomal recessive steroid-resistant nephrotic syndrome. Nat Genet 24:349–354
Büscher AK, Kranz B, Büscher R et al (2010) Immunosuppression and renal outcome in congenital and pediatric steroid-resistant nephrotic syndrome. Clin J Am Soc Nephrol 5:2075–2084
Chernin G, Vega-Warner V, Schoeb DS et al (2010) Genotype/phenotype correlation in nephrotic syndrome caused by WT1 mutations. Clin J Am Soc Nephrol 5:1655–1662
Cho HY, Lee JH, Choi HJ (2008) WT1 and NPHS2 mutations in Korean children with steroid-resistant nephrotic syndrome. Pediatr Nephrol 23:63–70
Demmer L, Primack W, Loik V et al (1999) Frasier syndrome: a cause of focal segmental glomerulosclerosis in a 46,XX female. J Am Soc Nephrol 10:2215–2218
Denamur E, Bocquet N, Baudouin V (2000) WT1 splice-site mutations are rarely associated with primary steroid resistant focal and segmental glomerulosclerosis. Kidney Int 57:1868–1872
Denamur E, Bocquet N, Mougenot B et al (1999) Mother-to-child transmitted WT1 splice-site mutation is responsible for distinct glomerular diseases. J Am Soc Nephrol 10:2219–2223
Denys P, Malvaux P, Van Den Berghe H (1967) Association of an anatomopathological syndrome of male pseudohermaphroditism, Wilms’ tumor, parenchymatous nephropathy and XX/XY mosaicism. Arch Fr Pédiatr 24:729–739
Devriendt K, Deloof E, Moerman P et al (1995) Diaphragmatic hernia in Denys-Drash syndrome. Am J Med Genet 57:97–101
Drash A, Sherman F, Hartmann WH (1970) A syndrome of pseudohermaphroditism, Wilms’ tumor, hypertension and degenerative renal disease. J Pediatr 76:585–593
Ehrich JHH, Geerlings C, Zivicnjak M et al (2007) Steroid-resistant idiopathic childhood nephrosis: overdiagnosed and undertreated. Nephrol Dial Transplant 22(8):2183–2193
Fijita S, Sugimoto K, Miyazawa T et al (2010) A female infant with Frasier syndrome showing splice site mutation in Wilm’s tumor gene (WT1) intron 9. Clin Nephrol 73(6):487–491
Frasier SD, Bashore RA, Mosier HD (1964) Gonadoblastoma associated with pure gonadal dysgenesis in monozygous twins. J Pediatr 64:740–745
Gellermann J, Stefanidis CJ, Mitsioni A et al (2010) Successful treatment of steroid-resistant nephrotic syndrome associated with WT1 mutations. Pediatr Nephrol 25:1285–1289
Haber DA, Buckler AJ, Glaser T et al (1990) An internal deletion within an 11p13 zinc finger gene contributes to the development of Wilms’ tumour. Cell 61:1257–1269
Haber DA, Sohn RL, Buckler AJ (1991) Alternative splicing and genomic structure of the Wilms’ tumor gene WT1. Proc Natl Acad Sci USA 88:9618–9622
Hamilton TB, Barilla KC, Romaniuk PJ (1995) High affinity binding sites for the Wilms’ tumor suppressor protein WT1. Nucleic Acids Res 23:277–284
Hinkes B, Wiggins RC, Gbadegesin R et al (2006) Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible. Nat Genet 38:1397–1405
Ito S, Ikeda M, Takata A (1999) Nephrotic syndrome and end stage disease with WT1 mutation detected at 3 years. Pediatr Nephrol 13:790–791
Ito S, Takata A, Hataya H et al (2001) Isolated diffuse mesangial sclerosis and Wilms’ tumor suppressor gene. J Pediatr 138:425–427
Jeanpierre C, Denamur E, Henry I (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
Klamt B, Koziell A, Poulat F et al (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
Laity JH, Dyson HJ, Wright PE (2000) Molecular basis for modulation of biological function by alternate splicing of the Wilms’ tumor suppressor protein. Proc Natl Acad Sci USA 97:11932–11935
Lowik MM, Groenen PJ, Levtchenko EN et al (2009) Molecular genetic analysis of podocyte genes in focal segmental glomerulosclerosis—a review. Eur J Pediatr 168:1291–1304
McTaggart SJ, Algar E, Chow CW et al (2001) Clinical spectrum of Denys–Drash and Frasier syndrome. Pediatr Nephrol 16:335–339
Megremis S, Mitsioni A, Mitsioni A et al (2009) Nucleotide variations in the NPHS2 gene in Greek children with steroid-resistant nephrotic syndrome (SRNS). Genet Test Mol Biomarkers 13(2):249–256
Mitchell PJ, Tjian R (1989) Transcriptional regulation in mammalian cells by sequence-specific DNA binding proteins. Science 245:371–378
Mucha B, Ozaltin F, Hinkes BG (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
Royer-Pokora B, Beier M, Henzler M (2004) Twenty-four new cases of WT1 germline mutations and review of the literature: genotype/phenotype correlations for Wilms’ tumor development. Am J Med Genet 127A:249–257
Ruf RG, Schultheiss M, Lichtenberger A et al (2004) Prevalence of WT1 mutations in a large cohort of patients with steroid resistant and steroid sensitive nephrotic syndrome. Kidney Int 66:564–570
Schumacher V, Scharer K, Wuhl E (1998) Spectrum of early onset nephrotic syndrome associated with WT1 missense mutations. Kidney Int 53:1594–1600
Scott RH, Walker L, Olsen OE, Levitt G, Kenney I, Maher E, Owens CM, Pritchard-Jones K, Craft A, Rahman N (2006) Surveillance for Wilms tumour in at-risk children: pragmatic recommendations for best practice. Arch Dis Child 91(12):995–999
Sinha A, Sharma S, Gulati A et al (2010) Frasier syndrome: early gonadoblastoma and cyclosporine responsiveness. Pediatr Nephrol 25:2171–2174
Stefanidis CJ, Querfeld U (2011) The podocyte as a target: cyclosporin A in the management of the nephrotic syndrome caused by WT1 mutations. Eur J Pediatr. doi:10.1007/s00431-011-1397-6
Tsuda M, Owada M, Tsuchiya M et al (1999) Wt1 nephropathy in a girl with normal karyotype (46XX). Clin Nephrol 51:62–63
The authors would like to thank the Greek Society of Families with Kidney Disease “ELPIDA” for the financial support as well as Stavroula Papadopoulou and Konstantina Pouliou for their technical assistance.
Financial and competing interest disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
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Megremis, S., Mitsioni, A., Fylaktou, I. et al. Broad and unexpected phenotypic expression in Greek children with steroid-resistant nephrotic syndrome due to mutations in the Wilms’ tumor 1 (WT1) gene. Eur J Pediatr 170, 1529–1534 (2011). https://doi.org/10.1007/s00431-011-1450-5