Altered fra/zs-Activational Properties of a Mutated WT1 Gene Product in a WAGR-associated Wilms' liimor1

WAGR syndrome is an acronym for a rare constellation of congenital abnormalities including predisposition to Wilms' tumor, Aniridia, Geni tourinary malformations, and mental Retardation. These congenital de fects are associated with a constitutional deletion affecting one copy of chromosome band Ilpl3, implicating the loss of one alÃ-elefrom a number of contiguous genes in this syndrome. Predisposition to Wilms' tumor and genitourinary abnormalities have been attributed to hemizygosity for the »77 tumor suppressor gene, a transcriptional represser that is normally expressed transiently during kidney development. Here we show that a Wilms' tumor arising in a child with WAGR syndrome contained a point mutation within the remaining U77 alÃ-ele.This mutation resulted in a glycine to aspartic acid substitution within the putative frans-activation domain of H77. converting the encoded protein from a transcriptional represser to an activator of its target DNA sequence. Thus, a critical amino acid substitution can alter the functional properties of WT1 and provide the "second hit" required for Wilms tumorigenesis.