WT1 (Wilms tumor suppressor gene)

1999-10-01   Manfred Gessler 

Theodor-Boveri-Institut fuer Biowissenschaften, Lehrstuhl Physiol. Chemie I, Am Hubland, D-97074 Wuerzburg, Germany

Identity

HGNC
LOCATION
11p13
LOCUSID
ALIAS
AWT1,GUD,NPHS4,WAGR,WIT-2,WT33
FUSION GENES

DNA/RNA

Description

10 exons spanning 48 kb of genomic DNA

Transcription

3 kb mRNA; four alternative splice forms: +/- exon 5 and alternative splice donor sites at exon 9

Proteins

Description

four major isoforms (429-449 aa) due to alternative splicing; there are eight minor isoforms resulting from different initiation sites (upstream CTG: 502-522 aa, downstream ATG: 303-323 aa)

Expression

kidney, spleen, mesothelia

Localisation

nuclear staining, either diffuse or in speckles, depending on isoform and mutations

Function

zinc finger transcription factor (4 C2H2-type fingers)

Homology

Sp1, Egr-1

Mutations

Germinal

various types of mutations, mostly affecting zinc fingers in exons 7-10. (WAGR syndrome, genito-urinary (GU) anomalies, Denys-Drash-syndrome, Frasier syndrome; see below)

Somatic

biallelic inactivation in Wilms tumors (<15%) and some mesotheliomas and granulosa cell tumors

Implicated in

Entity name
Wilms tumor
Disease
nephroblastoma of childhood
Prognosis
good with treatment according to NWTS or SIOP
Cytogenetics
11p13 deletions/translocations can be seen in some cases
Oncogenesis
up to 15% of tumors show mainly biallelic inactivation of WT1 through deletion or mutatio
Prognosis
poor
Cytogenetics
translocations, t(11;22)(p13;q12)
Fusion protein
With EWS: EWS-WT; in frame fusion of EWS exons 1-7 and WT1 exons 8-10
Entity name
Denys-Drash syndrome (DDS)
Disease
defined by: mesangial sclerosis with kidney failure (age 2 yrs), gonadal dysgenesis, risk of Wilms tumors
Prognosis
kidney failure at age 0-5 years
Hybrid gene
dominant negative mutations, especially missense mutations within the zinc fingers (aa 394 Arg -> Trp) but very few nonsense mutations
Oncogenesis
high risk of Wilms tumor development
Entity name
Frasier syndrome
Disease
defined by: complete gonadal dysgenesis, focal glomerular sclerosis, gonadoblastoma; in karyotypic females the syndrome may be limited to focal glomerular sclerosis with regular gonadal development and function
Prognosis
kidney failure at age 10-30 years
Hybrid gene
heterozygous point mutations of alternative splice donor site in exon 9 with imbalance of WT1 isoform ratio
Oncogenesis
gonadoblatoma may occur within streak gonads

Bibliography

Pubmed IDLast YearTitleAuthors
83829381993The expression of the Wilms' tumour gene, WT1, in the developing mammalian embryo.Armstrong JF et al
93988521997Donor splice-site mutations in WT1 are responsible for Frasier syndrome.Barbaux S et al
86214951996A non-AUG translational initiation event generates novel WT1 isoforms.Bruening W et al
21543351990Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus.Call KM et al
78626271995Characterization of the genomic breakpoint and chimeric transcripts in the EWS-WT1 gene fusion of desmoplastic small round cell tumor.Gerald WL et al
80195571994Infrequent mutation of the WT1 gene in 77 Wilms' Tumors.Gessler M et al
21547021990Homozygous deletion in Wilms tumours of a zinc-finger gene identified by chromosome jumping.Gessler M et al
16587871991Alternative splicing and genomic structure of the Wilms tumor gene WT1.Haber DA et al
94994251998Frasier syndrome is caused by defective alternative splicing of WT1 leading to an altered ratio of WT1 +/-KTS splice isoforms.Klamt B et al
77365911995Subnuclear localization of WT1 in splicing or transcription factor domains is regulated by alternative splicing.Larsson SH et al
90905241997A clinical overview of WT1 gene mutations.Little M et al
16552841991Germline mutations in the Wilms' tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome.Pelletier J et al
22442091990Binding of the Wilms' tumor locus zinc finger protein to the EGR-1 consensus sequence.Rauscher FJ 3rd et al
104385241999Internal translation initiation generates novel WT1 protein isoforms with distinct biological properties.Scharnhorst V et al
81709461994Fine structure analysis of the WT1 gene in sporadic Wilms tumors.Varanasi R et al

Other Information

Locus ID:

NCBI: 7490
MIM: 607102
HGNC: 12796
Ensembl: ENSG00000184937

Variants:

dbSNP: 7490
ClinVar: 7490
TCGA: ENSG00000184937
COSMIC: WT1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000184937ENST00000332351J3KNN9
ENSG00000184937ENST00000379077H0Y3F0
ENSG00000184937ENST00000379079P19544
ENSG00000184937ENST00000448076H0Y7K5
ENSG00000184937ENST00000452863A0A0A0MT54
ENSG00000184937ENST00000527882H0YED9
ENSG00000184937ENST00000530998P19544
ENSG00000184937ENST00000639563A0A1W2PQQ0
ENSG00000184937ENST00000640146A0A1W2PR07
ENSG00000184937ENST00000651459A0A494C0I9

Expression (GTEx)

0
50
100
150

Pathways

PathwaySourceExternal ID
Transcriptional misregulation in cancerKEGGko05202
Transcriptional misregulation in cancerKEGGhsa05202

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA445084Wilms TumorDiseaseDataAnnotation, Literature, MultilinkAnnotationassociated23788249

References

Pubmed IDYearTitleCitations
173719322007Nephrotic syndrome in the first year of life: two thirds of cases are caused by mutations in 4 genes (NPHS1, NPHS2, WT1, and LAMB2).119
153651882004Induction of WT1 (Wilms' tumor gene)-specific cytotoxic T lymphocytes by WT1 peptide vaccine and the resultant cancer regression.118
197523352009Real-time quantitative polymerase chain reaction detection of minimal residual disease by standardized WT1 assay to enhance risk stratification in acute myeloid leukemia: a European LeukemiaNet study.92
169878842006The many facets of the Wilms' tumour gene, WT1.90
221727222011WT1 mutants reveal SRPK1 to be a downstream angiogenesis target by altering VEGF splicing.88
254825562014DNA hydroxymethylation profiling reveals that WT1 mutations result in loss of TET2 function in acute myeloid leukemia.88
256017572015WT1 recruits TET2 to regulate its target gene expression and suppress leukemia cell proliferation.71
203685382010Impact of IDH1 R132 mutations and an IDH1 single nucleotide polymorphism in cytogenetically normal acute myeloid leukemia: SNP rs11554137 is an adverse prognostic factor.70
185598742008Wilms' tumor 1 gene mutations independently predict poor outcome in adults with cytogenetically normal acute myeloid leukemia: a cancer and leukemia group B study.68
185598742008Wilms' tumor 1 gene mutations independently predict poor outcome in adults with cytogenetically normal acute myeloid leukemia: a cancer and leukemia group B study.68

Citation

Manfred Gessler

WT1 (Wilms tumor suppressor gene)

Atlas Genet Cytogenet Oncol Haematol. 1999-10-01

Online version: http://atlasgeneticsoncology.org/gene/78/wt1