title: Altered trans-activational properties of a mutated WT1 gene product in a WAGR-associated Wilms' tumor.
abstract: 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.
authors.affiliation: Laboratory of Molecular Genetics, Massachusetts General Hospital Cancer Center, Charlestown.
authors.forename: S
authors.initials: S
authors.lastname: Park
authors.forename: G
authors.initials: G
authors.lastname: Tomlinson
authors.forename: P
authors.initials: P
authors.lastname: Nisen
authors.forename: D A
authors.initials: DA
authors.lastname: Haber
mesh_terms: D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D001224:Aspartic Acid; D001483:Base Sequence; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D002869:Chromosome Aberrations; D002880:Chromosomes, Human, Pair 11; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D017353:Gene Deletion; D016147:Genes, Tumor Suppressor; D005998:Glycine; D006801:Humans; D007621:Karyotyping; D007668:Kidney / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D017354:Point Mutation; D017624:WAGR Syndrome / Q000235:genetics* / Q000378:metabolism; D025721:WT1 Proteins; D009396:Wilms Tumor / Q000235:genetics* / Q000378:metabolism; D016335:Zinc Fingers / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D025721:WT1 Proteins; D001224:Aspartic Acid; D015500:Chloramphenicol O-Acetyltransferase; D005998:Glycine