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© 1995 Oxford University Press

RESEARCH-ARTICLE

DNA binding capacity of the WT1 protein is abolished by Denys—Drash syndrome WT1 point mutations

Melissa Little*, Gregory Holmes, Wendy Bickmore1, Veronica van Heyningen1, Nicholas Hastie1 and Brandon Wainwright

Centre for Molecular and Cellular Biology, University of Queensland St Lucia, Brisbane, Queensland 4072, Australia 1Medical Research Council Human Genetics Unit, Western General Hospital Crewe Road, Edinburgh EH4 2XU, Scotland, UK

*To whom correspondence should be addressed

Received October 3, 1994; Revised December 22, 1994; Accepted December 22, 1994

Constitutional point mutations in the zinc finger (ZF) region of the Wilms' tumour suppressor gene 1 (WT1) lead to Denys—Drash syndrome (DDS). Patients with this syndrome display renal failure, Wilms' tumour (WT) and pseudohermaphroditism. DDS WT1 mutations fall into three major categories: (a) missense mutations altering amino acids which directly interact with the DNA target; (b) substitution of amino acids involved in zinc complexing; and (c) nonsense mutations leading to the removal of at least two zinc fingers. We have expressed the WT1 zinc fingers as glutathione-S-transferase fusion proteins, with the lysine-threonine-serine (KTS) alternate splice between ZF3 and ZF4 either present or absent. WT1 fusion constructs with all three classes of DDS mutation were also created. Wild-type and mutant fusion proteins were assayed for their DNA-binding affinity using four previously identified WT1 DNA targets: an EGR1 consensus site; murine insulin-like growth factor 2 promoter 2 (IGF2P2); a (TCC)n motif from the PDGFA-chain promoter; and +P5, a genomic fragment isolated by its affinity for WT1+KTS. WT1-KTS bound all four targets, but WT1+KTS only bound +P5. All three classes of DDS mutation investigated, with or without KTS, abolished binding to all four targets. This provides evidence that DDS mutations act either as dominant-negative antimorphs, or elicit their effect through disturbed isoform dosage balance.


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