Abstract
Denys-Drash syndrome (DDS) is characterized by early onset nephropathy, pseudohermaphroditism in males and a high risk for developing Wilms' tumour (WT). The exact cause of DDS is unknown but germline mutations in the Wilms' tumour suppressor gene (WT1) have recently been described in the majority of DDS patients studied. These mutations occur de novo and are clustered around the zinc finger (ZF) coding exons of the WT1 gene. Analysis of exons 2–10 of the WT1 gene in constitutional DNA from five patients with DDS was carried out using the polymerase chain reaction (PCR) and direct DNA sequencing. In four out of the five patients, heterozygous germline mutations were found: a novel point mutation in exon 8 (ZF2) at codon 377 altering the wild-type histidine to arginine, and three previously described point mutations in exon 9 (ZF3) in the codons corresponding to amino acids 394Arg and 396Asp. In one patient, no mutations could be demonstrated. In three patients where parental DNA was available, the mutations were shown to have occurred de novo. Furthermore, since tumour DNA in two of these cases had lost the wild-type allele, polymorphic markers from the short arm of chromosome 11 were used to determine the parental origin of the mutant chromosome. In both cases, the mutant chromosome was shown to be of paternal origin. Since the majority of published WT1 mutations in DDS patients alter a RsrII restriction site in exon 9, we were able to perform PCR-based diagnosis in a female patient with early renal insufficiency and normal external genitalia.
Similar content being viewed by others
References
Baird PN, Santos A, Groves N, Jadresic L, Cowell JK (1992) Constitutional mutations in the WTI gene in patients with Denys-Drash syndrome. Hum Mol Genet 1:301–305
Bruening W, Bardeesy N, Silverman BL, Cohn RA, Machin GA, Aronson AJ, Housman D, Pelletier J (1992) Germline intronic and exonic mutations in the Wilms tumour gene (WTI) affecting urogenital development. Nature Genet 1:144–148
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
Coppes MJ, Liefers GJ, Higuchi M, Zinn AB, Balfe JW, Williams BRG (1993) Inherited WT1 mutation in Denys-Drash syndrome. Cancer Res 52:6125–6128
Denys P, Malvaux P, Berghe H van den, Tanghe 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, Hartmann WH, Blizzard RM (1979) A syndrome of pseudohermaphroditism, Wilm's tumor, hypertension, and degenerative renal disease. J Pediatr 76:585–593
Dryja TP, Mukai S, Petersen R, Rapaport JM, Walton D, Yandell DW (1989) Parental origin of mutations of the retinoblastoma gene. Nature 339:556–558
Ehrlich HA, Gelfand D, Sninsky JJ (1991) Recent advances in the polymerase chain reaction. Science 252:1643–1650
Gessler M, Poutska A, Cavenee W, Neve RL, Orkin SH, Bruns GAP (1990) Homozygous deletion in Wilms tumors of a zinc-finger gene identified by chromosome jumping. Nature 343:774–778
Gessler M, König A, Bruns GAP (1992) The genomic organization and expression of the WT1 gene. Genomics 12:807–813
Greer CE, Peterson SL, Kiviat NB, Manos MM (1991) PCR amplification from paraffin embedded tissue. Am J Clin Pathol 95:117–124
Haber DA, Buckler AJ, Glaser T, Call KM, Pelletier J, Sohn PL, Douglass EC, Housman DE (1990) An internal deletion within an 11p13 zinc finger gene contributes to the development of Wilms' tumor. Cell 61:1257–1269
Haber DA, Sohn RL, Buckler AJ, Pelletier J, Call KM, Housman DE (1991) Alternative splicing and genomic structure of the Wilms tumor gene WT1. Proc Natl Acad Sci USA 88:9618–9622
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
Huff V, Miwa H, Haber D, Call KM, Housman D, Strong LC, Saunders GF (1991) Evidence for WT1 as a Wilms tumor (WT) gene: intragenic germinal deletion in bilateral WT. Am J Hum Genet 48:997–1003
Julier C, Hyer RN, Davies J, Merlin F, Soularue P, Briant L, Cathelineau G, Deschamps I, Rotter JI, Froguel P, Boitard C, Bell JI, Lathrop GM (1991) Insulin-IGF2 region on chromosome 11p encodes a gene implicated in HLA-DR4-dependent diabetes susceptibility. Nature 354:155–159
Little MH, Prosser J, Condie A, Smith PJ, Heinigen V van, Hastie ND (1992) Zinc finger point mutations within the WT1 gene in Wilms tumor patients. Proc Natl Acad Sci USA 89:4791–4795
Little MH, Williamson KA, Mannens M, Kelsey A, Gosden C, Hastie ND, Heiningen V van (1993) Evidence that WT1 mutations in Denys-Drash syndrome patients may act in a dominant-negative fashion. Hum Mol Genet 2:259–264
Ogawa O, Eccles MR, Yun K, Mueller RF, Holdaway MDD, Reeve AE (1992) A novel insertional mutation at the third zinc finger coding region of the WT1 gene in Denys-Drash syndrome. Hum Mol Genet 2:203–204
Pal N, Wadey RB, Buckle B, Yeomans E, Pritchard J, Cowell JK (1990) Preferential loss of maternal alleles in sporadic Wilms' tumour. Oncogene 5:1665–1668
Pelletier J, Bruening W, Frederick PL, Haber DA, Glaser T, Housman DE (1991a) WT1 mutations contribute to abnormal genital system development and hereditary Wilms' tumour. Nature 353:431–434
Pelletier J, Bruening W, Kashtan CE, Mauer SM, Manivel JC, Striegel JE, Houghton DC, Junien C, Habib R, Fouser L, Fine RN, Silverman BL, Haber DA, Housman D (1991b) Germline mutations in the Wilms' tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome. Cell 67:437–447
Pritchard Jones K, Fleming S, Davidson D, Bickmore W, Porteous D, Gosden C, Bard J, Buckler A, Pelletier JJ, Housman D, Heinigen V van, Hastie N (1990) The candidate Wilms' tumour gene is involved in genitourinary development. Nature 346:194–197
Polymeropoulos M, Xiao H, Rath DS, Merril CR (1991) Tetranucleotide repeat polymorphism at the human tyrosine hydroxylase gene (TH). Nucleic Acids Res 19:3753
Poulat F, Morin D, König A, Giltay J, Sultan C, Dumas R, Gessler M, Berta P (1993) Distinct molecular origins for Denys-Drash and Frasier syndromes. Hum Genet 91:285–286
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Nordenskjöld, A., Friedman, E. & Anvret, M. WT1 mutations in patients with Denys-Drash syndrome: a novel mutation in exon 8 and paternal allele origin. Hum Genet 93, 115–120 (1994). https://doi.org/10.1007/BF00210593
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00210593