WT1 (Wilms tumor suppressor gene)

1999-10-01 Manfred Gessler Affiliation

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

Identity

HGNC

WT1

LOCATION

11p13

LOCUSID

7490

ALIAS

AWT1,GUD,NPHS4,WAGR,WIT-2,WT33

FUSION GENES

Show Gene Fusions

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 (

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

Entity name

desmoplastic small round cell tumor (DSRCT)

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 ID	Last Year	Title	Authors

Other Information

Locus ID:

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

Variants:

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

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000184937	ENST00000332351	J3KNN9
ENSG00000184937	ENST00000379077	H0Y3F0
ENSG00000184937	ENST00000379079	P19544
ENSG00000184937	ENST00000448076	H0Y7K5
ENSG00000184937	ENST00000452863	A0A0A0MT54
ENSG00000184937	ENST00000527882	H0YED9
ENSG00000184937	ENST00000530998	P19544
ENSG00000184937	ENST00000639563	A0A1W2PQQ0
ENSG00000184937	ENST00000640146	A0A1W2PR07
ENSG00000184937	ENST00000651459	A0A494C0I9

Expression (GTEx)

100

150

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Transcriptional misregulation in cancer	KEGG	ko05202
Transcriptional misregulation in cancer	KEGG	hsa05202

Protein levels (Protein atlas)

Not detected

Low

Medium

High

PharmGKB

Entity ID	Name	Type	Evidence	Association	PK	PD	PMIDs
PA445084	Wilms Tumor	Disease	DataAnnotation, Literature, MultilinkAnnotation	associated			23788249

References

Pubmed ID	Year	Title	Citations
17371932	2007	Nephrotic syndrome in the first year of life: two thirds of cases are caused by mutations in 4 genes (NPHS1, NPHS2, WT1, and LAMB2).	119
15365188	2004	Induction of WT1 (Wilms' tumor gene)-specific cytotoxic T lymphocytes by WT1 peptide vaccine and the resultant cancer regression.	118
19752335	2009	Real-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
16987884	2006	The many facets of the Wilms' tumour gene, WT1.	90
22172722	2011	WT1 mutants reveal SRPK1 to be a downstream angiogenesis target by altering VEGF splicing.	88
25482556	2014	DNA hydroxymethylation profiling reveals that WT1 mutations result in loss of TET2 function in acute myeloid leukemia.	88
25601757	2015	WT1 recruits TET2 to regulate its target gene expression and suppress leukemia cell proliferation.	71
20368538	2010	Impact of IDH1 R132 mutations and an IDH1 single nucleotide polymorphism in cytogenetically normal acute myeloid leukemia: SNP rs11554137 is an adverse prognostic factor.	70
18559874	2008	Wilms' tumor 1 gene mutations independently predict poor outcome in adults with cytogenetically normal acute myeloid leukemia: a cancer and leukemia group B study.	68
18559874	2008	Wilms' 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/gene-fusions-explorer/welcome