Changes

Wilms’ Tumor 1 (WT1) was originally cloned in 1990 as a tumour suppressor gene in Wilms’ tumor, a typically pediatric renal tumor (Call et al., 1990). A combination of alternative transcription and translation start sites, splicing, and RNA editing means that WT1 has many isoforms. Human WT1 spans up to 10 exons across multiple isoforms.

Wilms’ Tumor 1 (WT1) was originally cloned in 1990 as a tumour suppressor gene in Wilms’ tumor, a typically pediatric renal tumor (Call et al., 1990). A combination of alternative transcription and translation start sites, splicing, and RNA editing means that WT1 has many isoforms. Human WT1 spans up to 10 exons across multiple isoforms.

All WT1 isoforms contain four zinc finger regions at the C-terminus of the protein which are involved in DNA binding (Haber et al., 1991). The N-terminal region is comprised of proline-glutamine-rich sequences and is involved in RNA and protein interactions. A nine nucleotide (three amino acid – lysine, threonine, serine, or KTS) sequence exists at the 3’ end of exon 9. Alternative splicing leads to certain isoforms retaining or omitting the KTS sequence (Haber et al., 1991). Both +KTS and -KTS isoforms appear to have non-overlapping functions and are expressed in a specific ratio in normal cells (Haber et al., 1991; Hammes et al., 2001). Germline splice-site mutations resulting in reduced +KTS/-KTS ratios are responsible for Frasier syndrome (Barbaux et al., 1997). Alternative splicing of WT1 exon 5 also leads to some isoforms containing a 17 amino acid domain responsible for transcriptional activation through interaction with the prostate apoptosis response factor PAR4 (Richard et al., 2001).

All WT1 isoforms contain four zinc finger regions at the C-terminus of the protein which are involved in DNA binding (Haber et al., 1991). The N-terminal region is comprised of proline-glutamine-rich sequences and is involved in RNA and protein interactions. A nine nucleotide (three amino acid – lysine, threonine, serine, or KTS) sequence exists at the 3’ end of exon 9. Alternative splicing leads to certain isoforms retaining or omitting the KTS sequence (Haber et al., 1991). Both +KTS and -KTS isoforms appear to have non-overlapping functions and are expressed in a specific ratio in normal cells (Haber et al., 1991; Hammes et al., 2001). Germline splice-site mutations resulting in reduced +KTS/-KTS ratios are responsible for Frasier syndrome (Barbaux et al., 1997). Alternative splicing of WT1 exon 5 also leads to some isoforms containing a 17 amino acid domain responsible for transcriptional activation through interaction with the prostate apoptosis response factor PAWR (PAR4) (Richard et al., 2001).

WT1 is involved in cell growth and development. It has roles in, among others, the mesenchymal-to-epithelial transition during kidney and gonad development, the epithelial-to-mesenchymal transition during heart and diaphragm development, sensory neuron differentiation within the central nervous system, and adult tissue homeostasis (reviewed in (Hastie, 2017)). In the developing embryo it is expressed highly in the urogenital system, but in adults it can be found additionally in the central nervous system and in haematopoietic tissues (Menke et al., 1998). ''In vitro'' evidence suggests WT1 regulates ''BCL2'' and ''MYC'' expression, and interacts with TP53 (Hewitt et al., 1995; Maheswaran et al., 1993).

WT1 is involved in cell growth and development. It has roles in, among others, the mesenchymal-to-epithelial transition during kidney and gonad development, the epithelial-to-mesenchymal transition during heart and diaphragm development, sensory neuron differentiation within the central nervous system, and adult tissue homeostasis (reviewed in (Hastie, 2017)). In the developing embryo it is expressed highly in the urogenital system, but in adults it can be found additionally in the central nervous system and in haematopoietic tissues (Menke et al., 1998). ''In vitro'' evidence suggests WT1 regulates ''BCL2'' and ''MYC'' expression, and interacts with TP53 (Hewitt et al., 1995; Maheswaran et al., 1993).

Other than the tumours for which the gene is named, germline mutations affecting ''WT1'' also variously cause WAGR syndrome (Wilms’ tumour, aniridia, genitourinary anomalies and retardation) (Riccardi et al., 1978), Denys-Drash syndrome (DDS) (Pelletier et al., 1991), the previously mentioned Frasier syndrome, and less clearly Meacham syndrome (Suri et al., 2007).  

Other than the tumours for which the gene is named, germline mutations affecting ''WT1'' also variously cause WAGR syndrome (Wilms’ tumour, aniridia, genitourinary anomalies and retardation) (Riccardi et al., 1978), Denys-Drash syndrome (DDS) (Pelletier et al., 1991), the previously mentioned Frasier syndrome, and less clearly Meacham syndrome (Suri et al., 2007).

===Role in Cancer===

===Role in Cancer===