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01-10-2013 | Original Article

A familial WT1 mutation associated with incomplete Denys–Drash syndrome

Authors: Chunhua Zhu, Fei Zhao, Weizhen Zhang, Hongmei Wu, Ying Chen, Guixia Ding, Aihua Zhang, Songming Huang

Published in: European Journal of Pediatrics | Issue 10/2013

Abstract

Denys–Drash syndrome (DDS) is a rare disorder characterized by nephropathy, male pseudohermaphroditism, and wilms tumor. Cases are thought to arise sporadically through a de novo mutation in the wilms tumor suppressor gene (WT1), which encodes a zinc finger protein that not only acts as a tumor suppressor but is essential for normal gonadogenesis, nephrogenesis, and development of the urogenital tract. In this report, we describe a family with the well-known missense mutation in exon 9 of the WT1 gene, 1180C>T (R394W), causing incomplete DDS and no symptoms in their father. The proband, a boy with 46, XY karyotype, was born with ambiguous genitalia, penoscrotal hypospadias, and bilateral inguinal hernias. At 2 years of age, he has proteinuria and diffuse mesangial sclerosis, but no wilms tumor has been detected. The elder sister of the proband, at 3 years of age, has normal genitalia, proteinuria, focal mesangial sclerosis but no wilms tumor. The WT1 mutation was detected in both patients, who have suspected DDS, and their father, who is phenotypically normal. Conclusion: This case is unusual in that the 1180C>T mutation, which has been found in approximately 50 % of patients with complete DDS, has been inherited and is causing mild or no symptoms of DDS.

Akasaka Y, Kikuchi H, Nagai T, Hiraoka N, Kato S, Hata J (1993) A point mutation found in the WT1 gene in a sporadic wilms tumor without genitourinary abnormalities is identical with the most frequent point mutation in Denys–Drash syndrome. FEBS Lett 317:39–43PubMedCrossRef

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 1:301–305PubMedCrossRef

Bardeesy N, Zabel B, Schmitt K, Pelletier J (1994) WT1 mutations associated with incomplete Denys–Drash syndrome define a domain predicted to behave in a dominant-negative fashion. Genomics 21:663–664PubMedCrossRef

Benetti E, Caridi G, Malaventura C, Dagnino M, Leonardi E, Artifoni L, Ghiggeri GM, Tosatto SC, Murer L (2010) A novel WT1 gene mutation in a three-generation family with progressive isolated focal segmental glomerulosclerosis. Clin J Am Soc Nephrol: CJASN 5:698–702PubMedCrossRef

Coppes MJ, Liefers GJ, Higuchi M, Zinn AB, Balfe JW, Williams BR (1992) Inherited WT1 mutation in Denys–Drash syndrome. Cancer Res 52:6125–6128PubMed

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: JASN 10:2219–2223PubMed

Denys P, Malvaux P, Van Den Berghe H, Tanghe W, Proesmans W (1967) Association of an anatomo-pathological syndrome of male pseudohermaphroditism, wilms tumor, parenchymatous nephropathy, and XX/XY mosaicism. Arch Fr Pediatr 24:729–739PubMed

Drash A, Sherman F, Hartmann WH, Blizzard RM (1970) A syndrome of pseudohermaphroditism, wilms tumor, hypertension, and degenerative renal disease. J Pediatr 76:585–593PubMedCrossRef

Fencl F, Malina M, Stara V, Zieg J, Mixova D, Seeman T, Blahova K (2012) Discordant expression of a new WT1 gene mutation in a family with monozygotic twins presenting with congenital nephrotic syndrome. Eur J Pediatr 171:121–124PubMedCrossRef

10.

Gao F, Maiti S, Sun G, Ordonez NG, Udtha M, Deng JM, Behringer RR, Huff V (2004) The WT1+/R394W mouse displays glomerulosclerosis and early-onset renal failure characteristic of human Denys–Drash syndrome. Mol Cell Biol 24:9899–9910PubMedCrossRef

11.

Gessler M, Konig A, Bruns GA (1992) The genomic organization and expression of the WT1 gene. Genomics 12:807–813PubMedCrossRef

12.

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

13.

Heathcott RW, Morison IM, Gubler MC, Corbett R, Reeve AE (2002) A review of the phenotypic variation due to the Denys–Drash syndrome-associated germ line WT1 mutation R362X. Hum Mutat 19:462PubMedCrossRef

14.

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 62:824–833PubMedCrossRef

15.

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 7:709–714PubMedCrossRef

16.

Little S, Hanks S, King-Underwood L, Picton S, Cullinane C, Rapley E, Rahman N, Pritchard-Jones K (2005) A WT1 exon 1 mutation in a child diagnosed with Denys–Drash syndrome. Pediatr Nephrol 20:81–85PubMedCrossRef

17.

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

18.

Morrison AA, Viney RL, Ladomery MR (2008) The posttranscriptional roles of WT1, a multifunctional zinc-finger protein. Biochim Biophys Acta 1785:55–62PubMed

19.

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 59:325–331PubMedCrossRef

20.

Mueller RF (1994) The Denys–Drash syndrome. J Med Genet 31:471–477PubMedCrossRef

21.

Niaudet P, Gubler MC (2006) WT1 and glomerular diseases. Pediatr Nephrol 21:1653–1660PubMedCrossRef

22.

Ogawa O, Eccles MR, Yun K, Mueller RF, Holdaway MD, Reeve AE (1993) A novel insertional mutation at the third zinc finger coding region of the WT1 gene in Denys–Drash syndrome. Hum Mol Genet 2:203–204PubMedCrossRef

23.

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

24.

Pritchard-Jones K, Rahman N, Gerrard M, Variend D, King-Underwood L (2000) Familial wilms tumor resulting from WT1 mutation: intronic polymorphism causing artifactual constitutional homozygosity. J Med Genet 37:377–379PubMedCrossRef

25.

Ratelade J, Arrondel C, Hamard G, Garbay S, Harvey S, Biebuyck N, Schulz H, Hastie N, Pontoglio M, Gubler MC, Antignac C, Heidet L (2010) A murine model of Denys–Drash syndrome reveals novel transcriptional targets of WT1 in podocytes. Hum Mol Genet 19:1–15PubMedCrossRef

26.

Regev M, Kirk R, Mashevich M, Bistritzer Z, Reish O (2008) Vertical transmission of a mutation in exon 1 of the WT1 gene: lessons for genetic counseling. Am J Med Genet A 146A:2332–2336PubMedCrossRef

27.

Royer-Pokora B, Beier M, Henzler M, Alam R, Schumacher V, Weirich A, Huff V (2004) Twenty-four new cases of WT1 germ line mutations and review of the literature: genotype/phenotype correlations for wilms tumor development. Am J Med Genet A 127A:249–257PubMedCrossRef

28.

Zirn B, Wittmann S, Gessler M (2005) Novel familial WT1 read-through mutation associated with wilms tumor and slow progressive nephropathy. Am J Kidney Dis 45:1100–1104PubMedCrossRef

Title: A familial WT1 mutation associated with incomplete Denys–Drash syndrome
Authors: Chunhua Zhu
Fei Zhao
Weizhen Zhang
Hongmei Wu
Ying Chen
Guixia Ding
Aihua Zhang
Songming Huang
Publication date: 01-10-2013
Publisher: Springer Berlin Heidelberg
Published in: European Journal of Pediatrics / Issue 10/2013
Print ISSN: 0340-6199
Electronic ISSN: 1432-1076
DOI: https://doi.org/10.1007/s00431-013-2004-9

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A familial WT1 mutation associated with incomplete Denys–Drash syndrome

Abstract

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Abstract

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