The Wilms' tumor suppressor gene 1 (wt1) encodes a transcription factor belonging to the Early Growth Response (EGR) family of proteins. The gene produces an mRNA that is alternatively spliced to yield four different species. In this thesis, it is shown that the wt1 gene has two sites of translational initiation, an AUG codon and a CUG codon that is upstream of and in frame with the AUG codon. The combination of alternative initiation sites and alternatively spliced exons allows the gene to encode eight different isoforms. It was previously shown that heterozygous mutations of wt1, predicted to result in a reduction in dosage of WT1, are associated with a predisposition to Wilms' tumor and mild abnormalities of the genitourinary system. However, other mutations of wt1, primarily missense mutations predicted to disrupt the ability of WT1 to bind to DNA, are associated with the severe disease of Denys-Drash syndrome (DDS). To explain the different disease states associated with mutations of wt1, it has been suggested that the mutations in DDS individuals must be acting other than as null alleles, i.e. in a dominant or dominant-negative fashion. In this thesis, an individual with DDS is reported to have a splicing mutation of wt1, predicted to drastically alter the ratio of WT1 isoforms. Because no altered forms of WT1 are produced in this individual, we were able to eliminate the possibility that DDS is caused by a gain of function of mutated WT1. In this thesis it is also shown that WT1 can form dimers through a domain encoded by its first two exons, and that mutated WT1 proteins are able to antagonize the function of wild-type WT1 by binding to and inactivating the wild-type proteins. This dominant-negative activity is hypothesized to reduce the dosage of functional WT1 to very low levels and to thus cause the severe disease of DDS. The work reported in this thesis also shows that WT1 is imported into the nucleus by a signal contained within its first zinc finger
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.41990 |
| Date | January 1996 |
| Creators | Bruening, Wendy. |
| Contributors | Pelletier, Jerry (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Biochemistry.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001549411, proquestno: NQ29897, Theses scanned by UMI/ProQuest. |
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