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.
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We wish to dedicate this manuscript to the memory of patient C. B., who recently passed away owing to secondary complications of Denys-Drash syndrome. Although commonly referred to as Drash syndrome, we prefer the eponym of Denys-Drash syndrome, since this constellation of anomalies was first described by Denys et al. (1967). We thank Dr. Vincent Stanton for kindly reviewing pathological specimens, Drs. Tom Glaser and David Brook for helpful discussions and comments during the course of this work, and Drs. Walter Mushynski and Philippe Gros for critical review of the manuscript. We are grateful to Drs. David Munroe and Vikas Sukhatme for their kind gifts of pSP65-38A and p327, respectively. We are gratefully indebted to the patients, their families, and treating physicians for having participated in this study. J. P. wishes to thank the McGill Department of Biochemistry for use of facilities and space. J. P. was supported by a postdoctoral fellowship award from the Medical Research Council of Canada. D. A. H. was supported by National Cancer Institute Clinical Investigator Award 1K08CA 01356. This research was supported by NIH grant HG00299 awarded to D. E. H. and by National Cancer Institute and Medical Research Council of Canada grants to J: P.
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