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

Article Bibliography

Pubmed ID	Last Year	Title	Authors
8382938	1993	The expression of the Wilms' tumour gene, WT1, in the developing mammalian embryo.	Armstrong JF et al
9398852	1997	Donor splice-site mutations in WT1 are responsible for Frasier syndrome.	Barbaux S et al
8621495	1996	A non-AUG translational initiation event generates novel WT1 isoforms.	Bruening W et al
2154335	1990	Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus.	Call KM et al
7862627	1995	Characterization of the genomic breakpoint and chimeric transcripts in the EWS-WT1 gene fusion of desmoplastic small round cell tumor.	Gerald WL et al
8019557	1994	Infrequent mutation of the WT1 gene in 77 Wilms' Tumors.	Gessler M et al
2154702	1990	Homozygous deletion in Wilms tumours of a zinc-finger gene identified by chromosome jumping.	Gessler M et al
1658787	1991	Alternative splicing and genomic structure of the Wilms tumor gene WT1.	Haber DA et al
9499425	1998	Frasier syndrome is caused by defective alternative splicing of WT1 leading to an altered ratio of WT1 +/-KTS splice isoforms.	Klamt B et al
7736591	1995	Subnuclear localization of WT1 in splicing or transcription factor domains is regulated by alternative splicing.	Larsson SH et al
9090524	1997	A clinical overview of WT1 gene mutations.	Little M et al
1655284	1991	Germline mutations in the Wilms' tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome.	Pelletier J et al
2244209	1990	Binding of the Wilms' tumor locus zinc finger protein to the EGR-1 consensus sequence.	Rauscher FJ 3rd et al
10438524	1999	Internal translation initiation generates novel WT1 protein isoforms with distinct biological properties.	Scharnhorst V et al
8170946	1994	Fine 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 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
38158126	2024	EWSR1::WT1 Fusions in Neoplasms Other Than Conventional Desmoplastic Small Round Cell Tumor: Three Tumors Occurring Outside the Female Genital Tract.
38219185	2024	Familial focal segmental glomerulosclerosis associated with a WT1 gene missense mutation: A case report.
38300383	2024	WT1 and TP53 as valuable diagnostic biomarkers for relapse after hematopoietic stem cell transplantation in acute myeloid leukemia.
38383842	2024	MAP4K4 and WT1 mediate SOX6-induced cellular senescence by synergistically activating the ATF2-TGFβ2-Smad2/3 signaling pathway in cervical cancer.
38423183	2024	Inhibition of transcriptional coactivator YAP Impairs the expression and function of transcription factor WT1 in diabetic podocyte injury.
38588409	2024	Comprehensive Transcriptomic Analysis of EWSR1::WT1 Targets Identifies CDK4/6 Inhibitors as an Effective Therapy for Desmoplastic Small Round Cell Tumors.
38642153	2024	Overexpression of WT1 in all molecular subtypes of breast cancer and its impact on survival: exploring oncogenic and tumor suppressor roles of distinct WT1 isoforms.
38745948	2024	Homeobox regulator Wilms Tumour 1 is displaced by androgen receptor at cis-regulatory elements in the endometrium of PCOS patients.
38158126	2024	EWSR1::WT1 Fusions in Neoplasms Other Than Conventional Desmoplastic Small Round Cell Tumor: Three Tumors Occurring Outside the Female Genital Tract.
38219185	2024	Familial focal segmental glomerulosclerosis associated with a WT1 gene missense mutation: A case report.
38300383	2024	WT1 and TP53 as valuable diagnostic biomarkers for relapse after hematopoietic stem cell transplantation in acute myeloid leukemia.
38383842	2024	MAP4K4 and WT1 mediate SOX6-induced cellular senescence by synergistically activating the ATF2-TGFβ2-Smad2/3 signaling pathway in cervical cancer.
38423183	2024	Inhibition of transcriptional coactivator YAP Impairs the expression and function of transcription factor WT1 in diabetic podocyte injury.
38588409	2024	Comprehensive Transcriptomic Analysis of EWSR1::WT1 Targets Identifies CDK4/6 Inhibitors as an Effective Therapy for Desmoplastic Small Round Cell Tumors.
38642153	2024	Overexpression of WT1 in all molecular subtypes of breast cancer and its impact on survival: exploring oncogenic and tumor suppressor roles of distinct WT1 isoforms.

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/tumors-explorer/teaching-explorer/