title: Regulation of renal EGF receptor expression is normal in Denys-Drash syndrome.
abstract: In patients with Denys-Drash syndrome, mutations of the Wilms' tumor suppressor gene are associated with nephroblastomas and developmental abnormalities of the genital tract and renal glomerulus. Normally, the Wilms' tumor gene product (WT1) is expressed at high levels in visceral glomerular epithelial cells (VGEC) of the emerging fetal glomerulus. We demonstrate that WT1 could normally serve to suppress EGF receptor expression in VGEC, since immunoreactive EGF receptor is strikingly absent compared to epithelial cells of the emerging proximal and distal tubule, which lack WT1. When HEK293 cells were co-transfected with plasmids containing EGFR enhancer/promoter elements linked to a CAT reporter and plasmids containing WT1 cDNA, EGFR enhancer/promoter activity was suppressed by all wild-type WT1 isoforms, but not by deletion mutants of WT1 lacking normal zinc-finger or N-terminal domains. Surprisingly, plasmids expressing a Denys-Drash WT1 mutant (R394W) retained the ability to suppress EGFR promoter activity in this system. Furthermore, we found that immunoreactive EGFR was appropriately undetectable in glomeruli from a three-year-old girl with Denys-Drash syndrome and in sections of her Wilm's tumor. These data suggest that faulty suppression of EGFR cannot account for the abnormalities of glomerulogenesis seen in Denys-Drash patients.
authors.affiliation: McGill University, Department of Pediatrics, Montreal, Quebec, Canada.
authors.forename: C
authors.initials: C
authors.lastname: Vicanek
authors.forename: E
authors.initials: E
authors.lastname: Ferretti
authors.forename: C
authors.initials: C
authors.lastname: Goodyer
authors.forename: E
authors.initials: E
authors.lastname: Torban
authors.forename: P
authors.initials: P
authors.lastname: Moffett
authors.forename: J
authors.initials: J
authors.lastname: Pelletier
authors.forename: P
authors.initials: P
authors.lastname: Goodyer
mesh_terms: D002460:Cell Line; D002675:Child, Preschool; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D005333:Fetus / Q000166:cytology / Q000378:metabolism; D016162:Genes, Wilms Tumor / Q000235:genetics*; D005835:Genitalia / Q000002:abnormalities*; D006801:Humans; D007150:Immunohistochemistry; D007668:Kidney / Q000196:embryology / Q000378:metabolism*; D007678:Kidney Glomerulus / Q000002:abnormalities*; D009154:Mutation; D012016:Reference Values; D013577:Syndrome; D014162:Transfection; D009396:Wilms Tumor / Q000235:genetics* / Q000378:metabolism*
chemical_list: D066246:ErbB Receptors