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WT1 (Wilms' tumor suppressor gene)

Identity

HGNC (Hugo) WT1
LocusID (NCBI) 7490
Location 11p13
Location_base_pair Starts at 32409322 and ends at 32457081 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Local_order Cen-RAG1/2-CAT-CD59-WT1-RCN-PAX6-FSHB-tel

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

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
  

Other Solid tumors implicated (Data extracted from papers in the Atlas)

Solid Tumors AmeloblastomID5945 MedulloblastomaID5065 rhab5004 rhabID5004 blad5001
bladID5001

External links

Nomenclature
HGNC (Hugo)WT1   12796
Cards
AtlasWT1ID78
Entrez_Gene (NCBI)WT1  7490  Wilms tumor 1
GeneCards (Weizmann)WT1
Ensembl (Hinxton)ENSG00000184937 [Gene_View]  chr11:32409322-32457081 [Contig_View]  WT1 [Vega]
ICGC DataPortalENSG00000184937
cBioPortalWT1
AceView (NCBI)WT1
Genatlas (Paris)WT1
WikiGenes7490
SOURCE (Princeton)NM_000378 NM_001198551 NM_001198552 NM_024424 NM_024425 NM_024426
Genomic and cartography
GoldenPath (UCSC)WT1  -  11p13   chr11:32409322-32457081 -  11p13   [Description]    (hg19-Feb_2009)
EnsemblWT1 - 11p13 [CytoView]
Mapping of homologs : NCBIWT1 [Mapview]
OMIM106210   136680   156240   194070   194072   194080   256370   607102   608978   
Gene and transcription
Genbank (Entrez)AK093168 AK291736 BC032861 BC046461 BG718348
RefSeq transcript (Entrez)NM_000378 NM_001198551 NM_001198552 NM_024424 NM_024425 NM_024426
RefSeq genomic (Entrez)AC_000143 NC_000011 NC_018922 NG_009272 NT_009237 NW_001838022 NW_004929378
Consensus coding sequences : CCDS (NCBI)WT1
Cluster EST : UnigeneHs.591980 [ NCBI ]
CGAP (NCI)Hs.591980
Alternative Splicing : Fast-db (Paris)GSHG0005677
Alternative Splicing GalleryENSG00000184937
Gene ExpressionWT1 [ NCBI-GEO ]     WT1 [ SEEK ]   WT1 [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP19544 (Uniprot)
NextProtP19544  [Medical]
With graphics : InterProP19544
Splice isoforms : SwissVarP19544 (Swissvar)
Domaine pattern : Prosite (Expaxy)ZINC_FINGER_C2H2_1 (PS00028)    ZINC_FINGER_C2H2_2 (PS50157)   
Domains : Interpro (EBI)Wilms_tumour [organisation]   Wilms_tumour_N [organisation]   Znf_C2H2 [organisation]   Znf_C2H2-like [organisation]   Znf_C2H2/integrase_DNA-bd [organisation]  
Related proteins : CluSTrP19544
Domain families : Pfam (Sanger)WT1 (PF02165)    zf-C2H2 (PF00096)   
Domain families : Pfam (NCBI)pfam02165    pfam00096   
Domain families : Smart (EMBL)ZnF_C2H2 (SM00355)  
DMDM Disease mutations7490
Blocks (Seattle)P19544
PDB (SRS)1LU6    1XF7    2G7T    2G7V    2G7W    2G7X    2JP9    2JPA    2PRT    3HPJ    3MYJ   
PDB (PDBSum)1LU6    1XF7    2G7T    2G7V    2G7W    2G7X    2JP9    2JPA    2PRT    3HPJ    3MYJ   
PDB (IMB)1LU6    1XF7    2G7T    2G7V    2G7W    2G7X    2JP9    2JPA    2PRT    3HPJ    3MYJ   
PDB (RSDB)1LU6    1XF7    2G7T    2G7V    2G7W    2G7X    2JP9    2JPA    2PRT    3HPJ    3MYJ   
Human Protein AtlasENSG00000184937 [gene] [tissue] [antibody] [cell] [cancer]
Peptide AtlasP19544
HPRD06163
IPIIPI00019517   IPI00550100   IPI00935900   IPI00936595   IPI00935507   IPI00974284   IPI00853526   IPI00374173   IPI01009246   IPI00978338   IPI00977686   
Protein Interaction databases
DIP (DOE-UCLA)P19544
IntAct (EBI)P19544
FunCoupENSG00000184937
BioGRIDWT1
InParanoidP19544
Interologous Interaction database P19544
IntegromeDBWT1
STRING (EMBL)WT1
Ontologies - Pathways
Ontology : AmiGOnegative regulation of transcription from RNA polymerase II promoter  RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in positive regulation of transcription  vasculogenesis  ureteric bud development  branching involved in ureteric bud morphogenesis  kidney development  regulation of organ formation  sequence-specific DNA binding transcription factor activity  sequence-specific DNA binding transcription factor activity  RNA binding  protein binding  nucleus  nucleoplasm  nucleolus  cytoplasm  cytoplasm  cytoplasm  apoptotic DNA fragmentation  transcription, DNA-templated  regulation of transcription, DNA-templated  regulation of transcription, DNA-templated  regulation of transcription from RNA polymerase II promoter  germ cell development  thorax and anterior abdomen determination  heart development  sex determination  zinc ion binding  negative regulation of cell proliferation  RNA splicing  gonad development  male gonad development  tissue development  nuclear speck  negative regulation of translation  negative regulation of cell growth  adrenal gland development  male genitalia development  epithelial cell differentiation  glomerulus development  glomerular basement membrane development  adrenal cortex formation  camera-type eye development  negative regulation of apoptotic process  sequence-specific DNA binding  transcription regulatory region DNA binding  negative regulation of transcription, DNA-templated  positive regulation of transcription, DNA-templated  positive regulation of transcription, DNA-templated  positive regulation of transcription, DNA-templated  positive regulation of transcription from RNA polymerase II promoter  mesenchymal to epithelial transition  positive regulation of heart growth  diaphragm development  cardiac muscle cell fate commitment  visceral serous pericardium development  C2H2 zinc finger domain binding  cellular response to cAMP  cellular response to gonadotropin stimulus  metanephric mesenchyme development  glomerular visceral epithelial cell differentiation  glomerular visceral epithelial cell differentiation  posterior mesonephric tubule development  metanephric epithelium development  metanephric S-shaped body morphogenesis  negative regulation of metanephric glomerular mesangial cell proliferation  positive regulation of male gonad development  negative regulation of female gonad development  positive regulation of metanephric ureteric bud development  
Ontology : EGO-EBInegative regulation of transcription from RNA polymerase II promoter  RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in positive regulation of transcription  vasculogenesis  ureteric bud development  branching involved in ureteric bud morphogenesis  kidney development  regulation of organ formation  sequence-specific DNA binding transcription factor activity  sequence-specific DNA binding transcription factor activity  RNA binding  protein binding  nucleus  nucleoplasm  nucleolus  cytoplasm  cytoplasm  cytoplasm  apoptotic DNA fragmentation  transcription, DNA-templated  regulation of transcription, DNA-templated  regulation of transcription, DNA-templated  regulation of transcription from RNA polymerase II promoter  germ cell development  thorax and anterior abdomen determination  heart development  sex determination  zinc ion binding  negative regulation of cell proliferation  RNA splicing  gonad development  male gonad development  tissue development  nuclear speck  negative regulation of translation  negative regulation of cell growth  adrenal gland development  male genitalia development  epithelial cell differentiation  glomerulus development  glomerular basement membrane development  adrenal cortex formation  camera-type eye development  negative regulation of apoptotic process  sequence-specific DNA binding  transcription regulatory region DNA binding  negative regulation of transcription, DNA-templated  positive regulation of transcription, DNA-templated  positive regulation of transcription, DNA-templated  positive regulation of transcription, DNA-templated  positive regulation of transcription from RNA polymerase II promoter  mesenchymal to epithelial transition  positive regulation of heart growth  diaphragm development  cardiac muscle cell fate commitment  visceral serous pericardium development  C2H2 zinc finger domain binding  cellular response to cAMP  cellular response to gonadotropin stimulus  metanephric mesenchyme development  glomerular visceral epithelial cell differentiation  glomerular visceral epithelial cell differentiation  posterior mesonephric tubule development  metanephric epithelium development  metanephric S-shaped body morphogenesis  negative regulation of metanephric glomerular mesangial cell proliferation  positive regulation of male gonad development  negative regulation of female gonad development  positive regulation of metanephric ureteric bud development  
Pathways : BIOCARTAChaperones modulate interferon Signaling Pathway [Genes]    Overview of telomerase protein component gene hTert Transcriptional Regulation [Genes]   
Pathways : KEGGTranscriptional misregulation in cancer   
Protein Interaction DatabaseWT1
Wikipedia pathwaysWT1
Gene fusion - rearrangments
Rearrangement : COSMICEWSR1 [22q12.2]  -  WT1 [11p13]  
  [COSF186] [COSF187] [COSF188] [COSF189] [COSF190] [COSF191] [COSF192] [COSF193] [COSF194] 
  [COSF225] [COSF226] [COSF230] [COSF231] [COSF239] [COSF240] [COSF241] [COSF249] 
 
Rearrangement : TICdbEWSR1 [22q12.2]  -  WT1 [6q22.1]
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)WT1
snp3D : Map Gene to Disease7490
SNP (GeneSNP Utah)WT1
SNP : HGBaseWT1
Genetic variants : HAPMAPWT1
Exome VariantWT1
1000_GenomesWT1 
ICGC programENSG00000184937 
Cancer Gene: CensusWT1 
Somatic Mutations in Cancer : COSMICWT1 
CONAN: Copy Number AnalysisWT1 
Mutations and Diseases : HGMDWT1
Genomic VariantsWT1  WT1 [DGVbeta]
dbVarWT1
ClinVarWT1
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM106210    136680    156240    194070    194072    194080    256370    607102    608978   
MedgenWT1
GENETestsWT1
Disease Genetic AssociationWT1
Huge Navigator WT1 [HugePedia]  WT1 [HugeCancerGEM]
General knowledge
Homologs : HomoloGeneWT1
Homology/Alignments : Family Browser (UCSC)WT1
Phylogenetic Trees/Animal Genes : TreeFamWT1
Chemical/Protein Interactions : CTD7490
Chemical/Pharm GKB GenePA37395
Drug Sensitivity WT1
Clinical trialWT1
Cancer Resource (Charite)ENSG00000184937
Other databases
Other databaseWT1 mutation database
Other databasehttp://cancergenome.broadinstitute.org/index.php?tgene=WT1
Probes
Litterature
PubMed448 Pubmed reference(s) in Entrez
CoreMineWT1
iHOPWT1
OncoSearchWT1

Bibliography

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
 
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
 
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
 
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
 
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
 
The genomic organization and expression of the WT1 gene.
Gessler M, Knig A, Bruns GA
Genomics. 1992 ; 12 (4) : 807-813.
PMID 1572653
 
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
 
Infrequent mutation of the WT1 gene in 77 Wilms' Tumors.
Gessler M, Knig 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
 
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
 
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
 
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 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
 
A clinical overview of WT1 gene mutations.
Little M, Wells C
Human mutation. 1997 ; 9 (3) : 209-225.
PMID 9090524
 
Donor splice-site mutations in WT1 are responsible for Frasier syndrome.
Barbaux S, Niaudet P, Gubler MC, Grnfeld JP, Jaubert F, Kuttenn F, Fkt CN, Souleyreau-Therville N, Thibaud E, Fellous M, McElreavey K
Nature genetics. 1997 ; 17 (4) : 467-470.
PMID 9398852
 
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
 
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
 
REVIEW articlesautomatic search in PubMed
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Contributor(s)

Written10-1999Manfred Gessler

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 online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/WT1ID78.html

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indexed on : Fri Aug 8 11:19:57 CEST 2014

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