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Germline mutations in the Wilms' tumor suppressor gene are associated with abnormal urogenital development in

J Pelletier1, W Bruening, C E Kashtan

  • 1Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, 02139.

Cell
|October 18, 1991
PubMed

Insights

Denys-Drash syndrome, a condition causing kidney failure and pseudohermaphroditism, is linked to mutations in the Wilms' tumor suppressor gene (WT1). These WT1 gene mutations directly impact DNA recognition, affecting urogenital development.

Area of Science:

  • Genetics
  • Developmental Biology
  • Oncology

Background:

  • Denys-Drash syndrome is a rare disorder characterized by severe urogenital abnormalities, including renal failure, pseudohermaphroditism, and Wilms' tumor (nephroblastoma).
  • The Wilms' tumor suppressor gene (WT1) plays a critical role in urogenital development and tumor suppression.

Purpose of the Study:

  • To investigate the role of the Wilms' tumor suppressor gene (WT1) in the pathogenesis of Denys-Drash syndrome.
  • To identify specific mutations within the WT1 gene associated with Denys-Drash syndrome.

Main Methods:

  • Analysis of the coding exons of the WT1 gene for germline mutations in ten independent cases of Denys-Drash syndrome.
  • Genomic analysis to identify mutations affecting DNA sequence recognition within the zinc finger domains of WT1.
  • Investigation of allele status in tumor samples to assess for reduction to homozygosity.

Main Results:

  • Point mutations were identified in the zinc finger domains of one WT1 gene copy in all ten Denys-Drash syndrome cases.
  • Nine mutations were located in exon 9 (zinc finger III) and one in exon 8 (zinc finger II), directly impacting DNA sequence recognition.
  • Tumor samples from affected individuals showed reduction to homozygosity for the mutated WT1 allele, suggesting its role as a tumor suppressor.

Conclusions:

  • The findings provide direct evidence for a causal role of WT1 mutations in Denys-Drash syndrome.
  • Mutations in WT1 are implicated in abnormal urogenital system development and the development of Wilms' tumors.
  • WT1 mutations disrupt critical DNA recognition functions, leading to the complex phenotype of Denys-Drash syndrome.

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