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WT1 (Wilms' tumor suppressor gene)

Written1999-10Manfred Gessler
Theodor-Boveri-Institut fuer Biowissenschaften, Lehrstuhl Physiol. Chemie I, Am Hubland, D-97074 Wuerzburg, Germany

(Note : for Links provided by Atlas : click)

Identity

HGNC (Hugo) WT1
HGNC Alias symbWAGR
WIT-2
AWT1
NPHS4
HGNC Previous nameGUD
HGNC Previous nameWilms tumor 1
LocusID (NCBI) 7490
Atlas_Id 78
Location 11p13  [Link to chromosome band 11p13]
Location_base_pair Starts at 32387776 and ends at 32435539 bp from pter ( according to GRCh38/hg38-Dec_2013)  [Mapping WT1.png]
Local_order Cen-RAG1/2-CAT-CD59-WT1-RCN-PAX6-FSHB-tel
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
EWSR1 (22q12.2)::WT1 (11p13)WT1 (11p13)::EWSR1 (22q12.2)

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

Protein

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

Note
  
Entity 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 desmoplastic small round cell tumor (DSRCT)
Prognosis poor
Cytogenetics translocations, t(11;22)(p13;q12)
Abnormal Protein With EWS: EWS-WT; in frame fusion of EWS exons 1-7 and WT1 exons 8-10
  
  
Entity 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/Mutated 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 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/Mutated 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

The expression of the Wilms' tumour gene, WT1, in the developing mammalian embryo.
Armstrong JF, Pritchard-Jones K, Bickmore WA, Hastie ND, Bard JB
Mechanisms of development. 1993 ; 40 (1-2) : 85-97.
PMID 8382938
 
Donor splice-site mutations in WT1 are responsible for Frasier syndrome.
Barbaux S, Niaudet P, Gubler MC, Grünfeld JP, Jaubert F, Kuttenn F, Fékété CN, Souleyreau-Therville N, Thibaud E, Fellous M, McElreavey K
Nature genetics. 1997 ; 17 (4) : 467-470.
PMID 9398852
 
A non-AUG translational initiation event generates novel WT1 isoforms.
Bruening W, Pelletier J
The Journal of biological chemistry. 1996 ; 271 (15) : 8646-8654.
PMID 8621495
 
Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus.
Call KM, Glaser T, Ito CY, Buckler AJ, Pelletier J, Haber DA, Rose EA, Kral A, Yeger H, Lewis WH
Cell. 1990 ; 60 (3) : 509-520.
PMID 2154335
 
Characterization of the genomic breakpoint and chimeric transcripts in the EWS-WT1 gene fusion of desmoplastic small round cell tumor.
Gerald WL, Rosai J, Ladanyi M
Proceedings of the National Academy of Sciences of the United States of America. 1995 ; 92 (4) : 1028-1032.
PMID 7862627
 
Infrequent mutation of the WT1 gene in 77 Wilms' Tumors.
Gessler M, König A, Arden K, Grundy P, Orkin S, Sallan S, Peters C, Ruyle S, Mandell J, Li F
Human mutation. 1994 ; 3 (3) : 212-222.
PMID 8019557
 
Homozygous deletion in Wilms tumours of a zinc-finger gene identified by chromosome jumping.
Gessler M, Poustka A, Cavenee W, Neve RL, Orkin SH, Bruns GA
Nature. 1990 ; 343 (6260) : 774-778.
PMID 2154702
 
Alternative splicing and genomic structure of the Wilms tumor gene WT1.
Haber DA, Sohn RL, Buckler AJ, Pelletier J, Call KM, Housman DE
Proceedings of the National Academy of Sciences of the United States of America. 1991 ; 88 (21) : 9618-9622.
PMID 1658787
 
Frasier syndrome is caused by defective alternative splicing of WT1 leading to an altered ratio of WT1 +/-KTS splice isoforms.
Klamt B, Koziell A, Poulat F, Wieacker P, Scambler P, Berta P, Gessler M
Human molecular genetics. 1998 ; 7 (4) : 709-714.
PMID 9499425
 
Subnuclear localization of WT1 in splicing or transcription factor domains is regulated by alternative splicing.
Larsson SH, Charlieu JP, Miyagawa K, Engelkamp D, Rassoulzadegan M, Ross A, Cuzin F, van Heyningen V, Hastie ND
Cell. 1995 ; 81 (3) : 391-401.
PMID 7736591
 
A clinical overview of WT1 gene mutations.
Little M, Wells C
Human mutation. 1997 ; 9 (3) : 209-225.
PMID 9090524
 
Germline mutations in the Wilms' tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome.
Pelletier J, Bruening W, Kashtan CE, Mauer SM, Manivel JC, Striegel JE, Houghton DC, Junien C, Habib R, Fouser L
Cell. 1991 ; 67 (2) : 437-447.
PMID 1655284
 
Binding of the Wilms' tumor locus zinc finger protein to the EGR-1 consensus sequence.
Rauscher FJ 3rd, Morris JF, Tournay OE, Cook DM, Curran T
Science (New York, N.Y.). 1990 ; 250 (4985) : 1259-1262.
PMID 2244209
 
Internal translation initiation generates novel WT1 protein isoforms with distinct biological properties.
Scharnhorst V, Dekker P, van der Eb AJ, Jochemsen AG
The Journal of biological chemistry. 1999 ; 274 (33) : 23456-23462.
PMID 10438524
 
Fine structure analysis of the WT1 gene in sporadic Wilms tumors.
Varanasi R, Bardeesy N, Ghahremani M, Petruzzi MJ, Nowak N, Adam MA, Grundy P, Shows TB, Pelletier J
Proceedings of the National Academy of Sciences of the United States of America. 1994 ; 91 (9) : 3554-3558.
PMID 8170946
 

Citation

This paper should be referenced as such :
Gessler, M
WT1 (Wilms' tumor suppressor gene)
Atlas Genet Cytogenet Oncol Haematol. 1999;3(4):177-178.
Free journal version : [ pdf ]   [ DOI ]


Other Leukemias implicated (Data extracted from papers in the Atlas) [ 5 ]
  t(10;14)(q24;q11) TLX1::TRD::t(7;10)(q34;q24) TRB::HOX11
Classification of myelodysplastic syndromes 2015
Mixed phenotype acute leukemia (MPAL)
Pediatric T-Cell Acute Lymphoblastic Leukemia
Therapy-Related Hematopoietic Neoplasia


Other Cancer prone implicated (Data extracted from papers in the Atlas) [ 3 ]
  Denys-Drash syndrome (DDS) Frasier syndrome (FS) WAGR (Wilms' tumor/aniridia/genitourinary anomalies/mental retardation syndrome)


External links

Nomenclature
HGNC (Hugo)WT1   12796
LRG (Locus Reference Genomic)LRG_525
Cards
AtlasWT1ID78
Entrez_Gene (NCBI)WT1    WT1 transcription factor
AliasesAWT1; GUD; NPHS4; WAGR; 
WIT-2; WT33
GeneCards (Weizmann)WT1
Ensembl hg19 (Hinxton)ENSG00000184937 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000184937 [Gene_View]  ENSG00000184937 [Sequence]  chr11:32387776-32435539 [Contig_View]  WT1 [Vega]
ICGC DataPortalENSG00000184937
TCGA cBioPortalWT1
AceView (NCBI)WT1
Genatlas (Paris)WT1
SOURCE (Princeton)WT1
Genetics Home Reference (NIH)WT1
Genomic and cartography
GoldenPath hg38 (UCSC)WT1  -     chr11:32387776-32435539 -  11p13   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)WT1  -     11p13   [Description]    (hg19-Feb_2009)
GoldenPathWT1 - 11p13 [CytoView hg19]  WT1 - 11p13 [CytoView hg38]
ImmunoBaseENSG00000184937
Genome Data Viewer NCBIWT1 [Mapview hg19]  
OMIM106210   136680   156240   194070   194072   194080   256370   607102   608978   
Gene and transcription
Genbank (Entrez)AB971668 AK093168 AK291736 BC032861 BC046461
RefSeq transcript (Entrez)NM_000378 NM_001198551 NM_001198552 NM_001367854 NM_024424 NM_024425 NM_024426
Consensus coding sequences : CCDS (NCBI)WT1
Gene ExpressionWT1 [ NCBI-GEO ]   WT1 [ EBI - ARRAY_EXPRESS ]   WT1 [ SEEK ]   WT1 [ MEM ]
Gene Expression Viewer (FireBrowse)WT1 [ Firebrowse - Broad ]
GenevisibleExpression of WT1 in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)7490
GTEX Portal (Tissue expression)WT1
Human Protein AtlasENSG00000184937-WT1 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Conserved Domain (NCBI)WT1
Human Protein Atlas [tissue]ENSG00000184937-WT1 [tissue]
HPRD06163
Protein Interaction databases
BioGRIDWT1
STRING (EMBL)WT1
ZODIACWT1
Ontologies - Pathways
Litterature
PubMed499 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
EVEXWT1
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Fri Oct 8 21:30:51 CEST 2021

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