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Title: Evolutionary comparison in the vertebrate lineage of WT1, a Wilms' tumour predisposition gene
Author: Kent, Gillian R. L.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1994
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The WT1 gene was isolated by positional cloning as a candidate gene implicated to predisposition to the paediatric kidney cancer Wilms' tumour. Because of its early onset and histological resemblance to immature kidneys, Wilms' tumour was thought to arise from an aberration in the normal developmental pathway. From the amino acid sequence, WT1 was predicted to be a transcription factor with an N-terminal proline/glutamine rich transregulatory domain and four C-terminal TFIIIA-like zinc fingers. Two alternative splices have been found in the transcript, resulting in the insertion of 17aa or 3aa (KTS). Functional analysis has shown that WT1 is capable of sequence specific DNA binding and of regulating transcription. Analysis of WT1 mRNA in the developing embryo has shown a pattern of expression consistent with an important role in nephrogenesis, specifically an involvement in mesenchymal-epithelial cell transition. WT1 analysis in Wilms' tumours revealed that both functional copies are lost in about 10% of sporadic Wilms' tumours. This confirmed the role of WT1 as a tumour suppressor gene in at least some cases, (following Knudson's two hit hypothesis for tumorigenesis). Predisposition to Wilms' tumour can also be associated with developmental abnormalities, including genitourinary malformations. Expression of WT1 is seen in the earliest stages of gonad development and constitutionally heterozygous mutations in WT1 are frequently associated with genitourinary abnormalities. The most sever abnormalities, in Denys-Drash syndrome, have been linked to heterozygous constitutional WT1 missense mutations in the zinc fingers. The cloning of the mouse WT1 gene revealed a very high level of similarity to the human gene, as well as a very similar pattern of expression during development.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available