ALTERED TRANS-ACTIVATIONAL PROPERTIES OF A MUTATED WT1 GENE-PRODUCT IN A WAGR-ASSOCIATED WILMS-TUMOR

WAGR syndrome is an acronym for a rare constellation of congenital abn ormalities including predisposition to Wilms' tumor, Aniridia, Genitou rinary malformations, and mental Retardation. These congenital defects at-e associated with a constitutional deletion affecting one copy of chromosome band 11p13, implicating the loss of one allele from a numbe r of contiguous genes in this syndrome. Predisposition to Wilms' tumor and genitourinary abnormalities have been attributed to hemizygosity for the WT1 tumor suppressor gene, a transcriptional repressor that is normally expressed transiently during kidney development. Here we sho w that a Wilms' tumor arising in a child with WAGR syndrome contained a point, mutation within the remaining WT1 allele. This mutation resul ted in a glycine to aspartic acid substitution within the putative tra ns-activation domain of WT1, converting the encoded protein from a tra nscriptional repressor to an activator of its target DNA sequence. Thu s, a critical amino acid substitution can alter the functional propert ies of WT1 and provide the ''second hit'' required for Wilms tumorigen esis.