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Altered trans-Activational Properties of a Mutated WT1 Gene Product in a WAGR-associated Wilms' Tumor¹

Laboratory of Molecular Genetics, Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts 02129 [S. P., D. A. H.], and Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75235 [G. T., P. N.]

WAGR syndrome is an acronym for a rare constellation of congenital abnormalities including predisposition to Wilms' tumor, Aniridia, Genitourinary malformations, and mental Retardation. These congenital defects are associated with a constitutional deletion affecting one copy of chromosome band 11p13, implicating the loss of one allele from a number 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 show that a Wilms' tumor arising in a child with WAGR syndrome contained a point mutation within the remaining WT1 allele. This mutation resulted in a glycine to aspartic acid substitution within the putative trans-activation domain of WT1, converting the encoded protein from a transcriptional repressor 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.

¹ This work was supported by NIH Grant CA 58596 (D. A. H.) and by grants from the Mallinckrodt and Culpepper Foundations.

² Scholar of the James McDonnell Foundation. To whom requests for reprints should be addressed.

Received 7/19/93. Accepted 9/ 1/93.

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