title: Germline mutations in the Wilms' tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome.
abstract: Denys-Drash syndrome is a rare human condition in which severe urogenital aberrations result in renal failure, pseudohermaphroditism, and Wilms' tumor (nephroblastoma). To investigate its possible role, we have analyzed the coding exons of the Wilms' tumor suppressor gene (WT1) for germline mutations. In ten independent cases of Denys-Drash syndrome, point mutations in the zinc finger domains of one WT1 gene copy were found. Nine of these mutations are found within exon 9 (zinc finger III); the remaining mutation is in exon 8 (zinc finger II). These mutations directly affect DNA sequence recognition. In two families analyzed, the mutations were shown to arise de novo. Wilms' tumors from three individuals and one juvenile granulosa cell tumor demonstrate reduction to homozygosity for the mutated WT1 allele. Our results provide evidence of a direct role for WT1 in Denys-Drash syndrome and thus urogenital system development.
authors.affiliation: Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, 02139.
authors.forename: J
authors.initials: J
authors.lastname: Pelletier
authors.forename: W
authors.initials: W
authors.lastname: Bruening
authors.forename: C E
authors.initials: CE
authors.lastname: Kashtan
authors.forename: S M
authors.initials: SM
authors.lastname: Mauer
authors.forename: J C
authors.initials: JC
authors.lastname: Manivel
authors.forename: J E
authors.initials: JE
authors.lastname: Striegel
authors.forename: D C
authors.initials: DC
authors.lastname: Houghton
authors.forename: C
authors.initials: C
authors.lastname: Junien
authors.forename: R
authors.initials: R
authors.lastname: Habib
authors.forename: L
authors.initials: L
authors.lastname: Fouser
mesh_terms: D058186:Acute Kidney Injury / Q000235:genetics; D000595:Amino Acid Sequence; D001483:Base Sequence; D002461:Cell Line, Transformed; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D012734:Disorders of Sex Development / Q000235:genetics; D005091:Exons / Q000235:genetics; D005260:Female; D016162:Genes, Wilms Tumor / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D016133:Polymerase Chain Reaction; D013577:Syndrome; D014564:Urogenital Abnormalities; D025721:WT1 Proteins; D009396:Wilms Tumor / Q000235:genetics; D016335:Zinc Fingers / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D025721:WT1 Proteins