This gene encodes a transcription factor that contains four zinc finger motifs at the C-terminus and a proline / glutamine-rich DNA-binding domain at the N-terminus. It has an essential role in the normal development of the urogenital system, and it is mutated in a subset of patients with Wilms' tumor, the gene's namesake. Multiple transcript variants, resulting from alternative splicing at two coding exons, have been well characterized. There is also evidence for the use of non-AUG (CUG) translation initiation site upstream of, and in-frame with the first AUG, leading to additional isoforms.[9]
Mutations of Wilms' tumor suppressor gene1 (WT1) are associated with embryonic malignancy of the kidney, affecting around 1-9 in 100,000 infants.[11] It occurs in both sporadic and hereditary forms. Inactivation of WT1 causes Wilms tumour, and Denys-Drash syndrome (DDS), leading to nephropathy and genital abnormalities. The WT1 protein has been found to bind a host of cellular factors, e.g. p53, a known tumor suppressor.[7][12][13][14] Despite the name, WT1 mutation is found in only about 5-10% of Wilms Tumor cases.[15] Some other genes associated with this disease are BRCA2 and GPC3.
WT1 is mutated in a mutually exclusive manner with TET2, IDH1, and IDH2inacute myeloid leukemia.[16] TET2 can be recruited by WT1 to its target genes and activates WT1-target genes by converting 5mC into 5hmC residues at the genes’ promoters,[17] representing an important feature of a new regulatory WIT pathway linked to the development of AML.[18]
The serine protease HtrA2 binds to WT1 and it cleaves WT1 at multiple sites following the treatment with cytotoxic drugs.[19][20]
Using immunohistochemistry, WT1 protein can be demonstrated in the cell nuclei of 75% of mesotheliomas and in 93% of ovarian serous carcinomas, as well as in benign mesothelium and fallopian tubeepithelium. This allows these tumours to be distinguished from other, similar, cancers, such as adenocarcinoma. Antibodies to the WT1 protein, however, also frequently cross-react with cytoplasmic proteins in a variety of benign and malignant cells, so that only nuclear staining can be considered diagnostic.[21]
Mutation in WT1 causes predisposition to hernias.[22]
Editing is tissue specific and developmentally regulated. Editing shown to be restricted in testis and kidney in the rat.[35] Editing of this gene product has been found to occur in mice and rats as well as humans.[35][37]
The editing site is found at nucleotide position 839 found in exon 6 of the gene. It causes a codon change from a Proline codon (CCC) to a Leucine codon (CUC)[35]
The type of editing is a uridinetocytidine (U to C) base change. The editing reaction is thought to be an amidation of uridine which converts it to a cytidine. The relevance of this editing is unknown as is the enzyme responsible for this editing. The region where editing occurs like that of other editing sites, e.g., ApoB mRNA editing is conserved. Mice, rats and humans have conserved sequences flanking the editing site consisting of 10 nucleotides before the editing site and four after the site.[35]
RNA editing results in an alternative amino acid being translated.[35] The changes in amino acid occur in a region identified as a domain involved in transcription activation function.[38]
Editing has been shown to decrease repressive regulation of transcription of growth promoting genes in vitro compared to the non edited protein. Although the physiological role of editing has yet to be determined, suggestions have been made that editing may play a role in the pathogenesis of Wilms tumour.[37]
WT1 gene can be found as well in the genomeofmice. The mouse model with a WT1 knock-out shows symptoms corresponding to human pathophysiology. The mice were observed to have defects of urogenital tract similar to cases patients when WT1 signalling has been malfunctioning.[29] The mouse had absent kidneys as their development failed during embryonic stages. This suggests that WT1 is unconditionally required for a proper kidney formation and development.[39]
Mouse model is used to study some specific disorder connected with WT1 expression, too, such as acute myeloid leukemia.[40] To examine the expression levels and localisation of WT1, a mouse model using WT1-GFP (green fluorescent protein) knock-in has been made. This model showed, that WT1 is significantly overexpressed in leukemic cells compared to none or minor expression in normal untransformed cells from bone marrow, either hematopoietic stem cellsorhematopoieticprogenitors and precursors.[41]
^Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH (February 1990). "Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus". Cell. 60 (3): 509–20. doi:10.1016/0092-8674(90)90601-A. PMID2154335. S2CID29092372.
^Oka Y, Tsuboi A, Kawakami M, Elisseeva OA, Nakajima H, Udaka K, Kawase I, Oji Y, Sugiyama H (2006). "Development of WT1 peptide cancer vaccine against hematopoietic malignancies and solid cancers". Current Medicinal Chemistry. 13 (20): 2345–52. doi:10.2174/092986706777935104. PMID16918359.
Lim HN, Hughes IA, Hawkins JR (December 2001). "Clinical and molecular evidence for the role of androgens and WT1 in testis descent". Molecular and Cellular Endocrinology. 185 (1–2): 43–50. doi:10.1016/S0303-7207(01)00631-1. PMID11738793. S2CID44309863.
