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RESEARCH-ARTICLE |
Evidence that WT1 mutations in Denys — Drash syndrome patients may act in a dominant-negative fashion
MRC Human Genetics Unit, Western General Hospital Crewe Road, Edinburgh EH4 2XU, UK 1Institute of Human Genetics (AMC), University of Amsterdam Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands 2Department of Pathology, Royal Manchester Children's Hospital Pendlebury, Manchester M27 1HA, UK
*To whom correspondence should be addressed
The triad of nephropathy, partial gonadal dysgenesis and Wilms' tumour (WT) is known as Denys — Drash syndrome (DDS). The WT predisposition gene WT1, which plays a vital role in both genital and renal development, is known to be mutated in DDS patients. The WT1 mutations in these patients are constitutional point mutations clustered in the zinc finger (ZF) encoding exons, particularly the exons encoding ZF2 and ZF3. The predicted functional alteration in WT1 is thought to underlie DDS aetiology either by abolishing binding of the WT1 ZF domain to its normal target DNA binding site(s), perhaps blocking the binding of the wild type WT1 present (dominant negative mutation), and/or by conferring the ability to recognise novel but inappropriate DNA binding sites (dominant mutation). We report here on the analysis of WT1 in a further five cases of DDS. In each case a constitutional point mutation was detected in either ZF2 or ZF3. Three of these mutations are novel, with two affecting the conserved histidine and cysteine residues crucial for ZF tertiary structure. The protein product of the third is predicted to lack ZF2, 3 and 4 as a result of a chain termination mutation, and is presumably incapable of binding DNA. However since the DDS phenotype is only elicited by mutations which lead to loss or alteration of ZF function (presumably DNA binding) while the N-terminal upstream portion of the gene remains intact, we suggest that a dominant negative mechanism is at work here.
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