Abstract
Constitutional missense mutations in the WT1 gene are usually associated with the Denys-Drash syndrome, characterized by a rapid progressive nephropathy, male pseudohermaphroditism, and an increased risk for Wilms tumor. We report here a patient with scrotal hypospadias and a slow progressive nephropathy due to focal and segmental glomerulosclerosis. WT1 mutation analysis revealed a constitutional missense mutation in exon 9 resulting in an exchange F392L. This mutation has previously been reported by others in a patient with a similar mild course of nephropathy. In contrast, a mutation in the corresponding codon of exon 8 (F364L) was previously found by us in a patient with a very rapid progression to end-stage renal disease. Whether the position of a mutation may influence the course of the nephropathy must be evaluated in a larger patient cohort. The individual tumor risk for this alteration cannot be given at present because neither of the two patients has shown evidence of a Wilms tumor or a gonadoblastoma to date.
References
Denys P, Malvaux P, Van den Berghe H, Tangue W, Proesmans W (1967) Association d’un syndrome anatomo-pathologique de pseudohermaphroditisme masculin, d’une tumeur de Wilms, d’une nephropathie parenchymateuse et d’un mosaicisme XX/XY. Arch Fr Pediatr 24:729–739
Drash A, Sherman F, Hartman WH, Blizzard RM (1970) A syndrome of pseudohermaphroditism, Wilms’ tumor, hypertension and degenerative renal disease. J Pediatr 76:585–593
Frasier SD, Bashore RA, Mosier HD (1964) Gonadoblastoma associated with pure gonadal dysgenesis in monozygotic twins. J Pediatr 64:740–745
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 3:297–302
Koziell A, Charmandari E, Hindmarsh PC, Rees L, Scambler P, Brook CGD (2000) Frasier syndrome, part of the Denys Drash continuum or simply a WT1 gene associated disorder of intersex and nephropathy? Clin Endocrinol (Oxf) 52:519–524
McTaggart SJ, Algar E, Chow CW, Powell HR, Jones CL (2001) Clinical spectrum of Denys-Drash and Frasier syndrome. Pediatr Nephrol 16:335–339
Pelletier J, Bruening W, Kashtan CE, Mauer SM, Manivel JC, Striegel JE, Houghton D, Junien C, Habib R, Fouser L, Fine RN, Silverman BL, Haber DA, Housman D (1991) Germline mutations in the Wilms’ tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome. Cell 67:437–447
Barbaux S, Niaudet P, Gubler MC, Grundfeld J-P, 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
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
Schumacher V, Schneider S, Figge A, Wildhardt G, Harms D, Schmidt D, Weirich A, Ludwig R, Royer-Pokora B (1997) Correlation of germ-line mutations and two hit inactivation of the WT1 gene with Wilms tumors of stromal-predominant histology. Proc Natl Acad Sci 94:3972–3977
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
Rauscher FJ (1993) The WT1 Wilms tumor gene product: a developmentally regulated transcription factor in the kidney that functions as a tumor suppressor. FASEB J 7:896–903
Schumacher V, Schärer K, Wühl E, Altrogge H, Bonzel K-E, Guschmann M, Neuhaus TJ, Pollastro RM, Kuwertz-Bröking E, Bulla M, Tondera A-M, Mundel P, Helmchen U, Waldherr R, Weirich A, Royer-Pokora B (1998) Spectrum of early onset nephrotic syndrome associated with WT1 missense mutations. Kidney Int 53:1594–1600
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 24:269–278
Jeanpierre C, Denamur E, Henry I, Cabanis MO, Luce S, Cécille A, Elion J, Peuchemaur 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
Heathcott RW, Morison IM, Gubler MC, Corbett R, Reeve AE (2002) A review of the phenotypic variation due to the Denys-Drash syndrome-associated germline WT1 mutation R362X. Hum Mutat 19:462
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Petras Kaltenis and Valérie Schumacher contributed equally to the work
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Kaltenis, P., Schumacher, V., Jankauskienė, A. et al. Slow progressive FSGS associated with an F392L WT1 mutation. Pediatr Nephrol 19, 353–356 (2004). https://doi.org/10.1007/s00467-003-1372-1
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DOI: https://doi.org/10.1007/s00467-003-1372-1