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A zinc finger truncation of murine WT1 results in the characteristic urogenital abnormalities of Denys-Drash syndrome

Lookup NU author(s): Dr Colin Miles, Dr James Doig

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Abstract

The Wilms tumor-suppressor gene, WT1, plays a key role in urogenital development, and WT1 dysfunction is implicated in both neoplastic (Wilms tumor, mesothelioma, leukemias, and breast cancer) and nonneoplastic (glomerulosclerosis) disease. The analysis of diseases linked specifically with WT1 mutations, such as Denys–Drash syndrome (DDS), can provide valuable insight concerning the role of WT1 in development and disease. DDS is a rare childhood disease characterized by a nephropathy involving mesangial sclerosis, XY pseudohermaphroditism, andyor Wilms tumor (WT). DDS patients are constitutionally heterozygous for exonic point mutations in WT1, which include mutations predicted to truncate the protein within the Cterminal zinc finger (ZF) region. We report that heterozygosity for a targeted murine Wt1 allele, Wt1tmT396, which truncates ZF3 at codon 396, induces mesangial sclerosis characteristic of DDS in adult heterozygous and chimeric mice. Male genital defects also were evident and there was a single case of Wilms tumor in which the transcript of the nontargeted allele showed an exon 9 skipping event, implying a causal link between Wt1 dysfunction and Wilms tumorigenesis in mice. However, the mutant WT1tmT396 protein accounted for only 5% of WT1 in both heterozygous embryonic stem cells and the WT. This has implications regarding the mechanism by which the mutant allele exerts its effect.


Publication metadata

Author(s): Patek CE, Little MH, Fleming S, Miles C, Charlieu JP, Clarke AR, Miyagawa K, Christie S, Doig J, Harrison DJ, Porteous DJ, Brookes AJ, Hooper ML, Hastie ND

Publication type: Article

Publication status: Published

Journal: Proceedings of the National Academy of Sciences of the United States of America

Year: 1999

Volume: 96

Issue: 6

Pages: 2931-2936

Print publication date: 16/03/1999

ISSN (print): 1091-6490

ISSN (electronic): 0027-8424

Publisher: National Academy of Sciences

URL: http://dx.doi.org/10.1073/pnas.96.6.2931

DOI: 10.1073/pnas.96.6.2931


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