title: Mice lacking the 68-amino-acid, mammal-specific N-terminal extension of WT1 develop normally and are fertile.
abstract: Mutations in the Wilms' tumor 1 gene, WT1, cause pediatric nephroblastoma and the severe genitourinary disorders of Frasier and Denys-Drash syndromes. High levels of WT1 expression are found in the developing kidney, uterus, and testis--consistent with this finding, the WT1 knockout mouse demonstrates that WT1 is essential for normal genitourinary development. The WT1 gene encodes multiple isoforms of a zinc finger-containing protein by a combination of alternative splicing and alternative translation initiation. The use of an upstream, alternative CUG translation initiation codon specific to mammals results in the production of WT1 protein isoforms with a 68-amino-acid N-terminal extension. To determine the function in vivo of mammal-specific WT1 isoforms containing this extension, gene targeting was employed to introduce a subtle mutation into the WT1 gene. Homozygous mutant mice show a specific absence of the CUG-initiated WT1 isoforms yet develop normally to adulthood and are fertile. Detailed histological analysis revealed normal development of the genitourinary system.
authors.affiliation: Medical Research Council Human Genetics Unit, Western General Hospital, Edinburgh EH4 2XU, United Kingdom.
authors.forename: Colin G
authors.initials: CG
authors.lastname: Miles
authors.forename: Joan
authors.initials: J
authors.lastname: Slight
authors.forename: Lee
authors.initials: L
authors.lastname: Spraggon
authors.forename: Maureen
authors.initials: M
authors.lastname: O'Sullivan
authors.forename: Charles
authors.initials: C
authors.lastname: Patek
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Hastie
mesh_terms: D000595:Amino Acid Sequence / Q000235:genetics*; D000818:Animals; D030321:Denys-Drash Syndrome / Q000235:genetics; D005260:Female; D005298:Fertility / Q000235:genetics*; D018390:Gene Targeting; D006720:Homozygote; D008297:Male; D008322:Mammals; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009928:Organ Specificity; D010641:Phenotype; D020033:Protein Isoforms / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics; D017384:Sequence Deletion / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D013045:Species Specificity; D025721:WT1 Proteins / Q000096:biosynthesis / Q000235:genetics*; D009396:Wilms Tumor / Q000235:genetics
chemical_list: D020033:Protein Isoforms; D025721:WT1 Proteins