Study of genotype/phenotype relationships involving the Wilms' tumor (WT) gene, WTI, in WT patients has provided insights into the function of the WT1 protein, a transcriptional regulator, and has suggested possible mutational mechanisms important in theetiologyof WT. For example, the identification of deletiodinsertion mutations in the first exon implicates a deletion hotspot consensus sequence in the etiology of these mutations. The disproportionate number of WT/aniridia patients with such mutations further suggest that this genetic mechanism may be enhanced by the hemizygous state. WT1 mutations are observed throughout the gene and, as predicted by the two-hit mutational model, germline mutations predominantly occur in patients with congenital genitourinary (GU) anomalies and/or bilateral disease. The presence of hemizygous mutations in tumors from individuals with germline 11 p l 3 deletions encompass-ing WTl supports the hypothesis that inactivation of both WT7 alleles is important in tumorigenesis.
Analyses of WT? mutations in individuals with WT-associated Drash syndrome and Wr patients with GU anomalies in the absence of Drash syndrome indicate that Drash patients almost invariably carry germline missense mutations in the zinc finger domains whereas WT/ G U patients carry germline mutations that delete the WT7 gene or encode truncated proteins. These data suggest a functional difference between mutant WT1 protein carrying a single amino acid substitution versus mutant WTl protein that is grossly truncated or WTl haploinsufficiency.
These and other genotype/phenotype correlations in WT patients will be discussed in more detail.