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FLASH GENE

Symbol

WT1

contributors: mct/pgu - updated : 31-01-2017

HGNC name	Wilms tumor 1
HGNC id	12796

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	DDS Denys Drash syndrome FS Frasier syndrome GUD genitourinary dysplasia component of WAGR syndrome IDMS nephrotic syndrome with an isolated diffuse or, rarely, a focal segmental mesangial sclerosis NPHS4 childhood nephrotic syndrome 4 SRN4 steroid-resistant nephrotic syndrome 4 WAGR WAGR complex
Location	11p13      Physical location : 32.409.324 - 32.457.087
Synonym name	wilms tumor protein
Synonym symbol(s)	WIT-2, WT33, AWT1, EWS-WT1, GUD, NPHS4, WAGR,

DNA

TYPE	functioning gene
SPECIAL FEATURE
text	WIT1 overlapping 5' - WT1
STRUCTURE	47.76 kb     10 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence	Promoter
	Binding site
text structure	several potential binding sites for ETV4 (activation of the WT1promoter) ; antisens regulatory region (WT1 ARR) contains a transcriptional silencer element acting on AWT1 and WT1-As imprinted transcripts

MAPPING

cloned

Y

linked

N

status

confirmed

RNA

TRANSCRIPTS	type	messenger

text	four variants generated by alternative splicing of exon 5 and the KTS sequence between zinc fingers 3 and 4 in exon 9, other alternative isoforms with different initiation sites

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_024425 9 - 2978 NP_077743 54.4 500 - 2003 12665546 also called variant C lacking exon 5 but containing the KTS sequence at the end of exon 9 initiation of translation like variant A NM_000378 9 splicing 2969 NP_000369 54.1 497 - 2003 12665546 also called varaiant A lacking exon 5 and the sequence encoding KTS at the end of exon 9 initiating translation from a non-AUG (CUG) site and also from a downstream in frame AUG NM_024424 10 splicing 3020 NP_077742 55.8 514 - 2003 12665546 also called variant B deletion of 3 AA, contains all ten exons but does not contain the additional sequence added to exon 9 initiation of translation like variant A NM_001198551 10 splicing 2480 NP_001185480 - 302 less abundant 2010 20591825 exon 5 /- KTS deletion of 20 AA acts mainly as a transcriptional factor, binding GC-rich DNA sequences with a high affinity specific interaction with ZNF224 NM_001198552 9 - 2438 NP_001185481 33 288 in renal and hematopoietic cells, maternally imprinting in the kidney 2004 14681303 also called AWT1 a new 5' exon in intron 1 NM_024426 10 - 3029 NP_077744 56.1 517 - 2010 20591825 also called variant D, + KTS contains ten exon and the additional sequence coding for KTS at the end of exon 9 translation initiation like variant A displays little affinity for DNA present in nuclear domains rich in splicing factors and has been found associated with snRNPs

EXPRESSION

Type	restricted

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular heart         Mus musculus Fetal Digestive salivary gland         Reproductive female system ovary         female system uterus         male system testis       Homo sapiens Fetal Urinary kidney nephron renal capsule     Homo sapiens Adult

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Connective bone       Epithelial barrier lining mesothelium     Homo sapiens Fetal

cells

System Cell Pubmed Species Stage Rna symbol Lymphoid/Immune lymphocyte Reproductive Sertoli cell Homo sapiens Fetal Urinary podocyte Homo sapiens Adult

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

fetal

Text	highly, in developing kidney, located in condensing mesenchyme
	in the developing kidney, with CXXC5 are coexpressed in podocytes of maturing nephrons
	specifically expressed in Sertoli cells in the developing testis

IMPRINTING	maternally, paternally
text	sometimes paternally imprinted in placenta and fetal brain, but maternally imprinted in fibroblasts and lymphocytes

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	a N-terminal transactivation domain proline endoglutamic rich
	four C terminal zinc fingers (C2H2 type)
	a KTS motif between ZF3 and ZF4
	nuclear translocation of WT1 involves KPNA2, KPNB1 and a NLS in the third zinc finger

HOMOLOGY

interspecies	homolog to murine Wt1 (97.5pc)
	homolog to rattus Wt1 (97.1pc)

Homologene

FAMILY

EGR C2H2-type zinc-finger protein family

CATEGORY

regulatory , transcription factor , tumor suppressor

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm
	intracellular,nucleus,nucleoplasm,nuclear bodies,nuclear speckles
	intracellular,nucleus,nucleolus
text	nuclear diffuse (-Kts), speckles (+Kts)
	shuttles between the nucleus and cytoplasm
	undergoing nucleocytoplasmic shuttling, and cytoplasmic WT1 was higher in malignant than in normal cells

basic FUNCTION	first considered as a repressor but appearing now as a transcriptional activator of specific genes i.e AMH and implicated in gonadal differentiation
	contributing to breast cancer progression by promoting breast cancer cell proliferation
	zinc finger protein playing a role in urogenital development and occurrence of glomerulosclerosis (regulation of podocyte function)
	may have an important role in tumorigenesis of various types of bone and soft-tissue sarcomas
	required for SOX9 expression and maintenance of tubular architecture in the developing testis
	may be an important component of the nitric oxide-dependent regulation of T lymphocyte proliferation and potential function
	crucial role in the generation of mesenchymal cardiovascular progenitor cells in the epicardium and during embryonic stem cell differentiation, through direct regulation of the SNAI1 transcription factor and E-cadherin
	activates CXXC5 transcription through the upstream enhancer region
	negatively regulates WNT/beta-catenin pathway via its target gene CXXC5
	novel immune regulatory function of WT1 in controlling IL10 gene expression
	WT1 and BASP1 can divert the lineage potential of an established blood cell line towards a cell with neuronal characteristics
	critically regulates epicardial RA signalling via direct activation of the ALDH1A2 gene
	role for WT1 in the regulation of morphogen receptors involved in the proliferation, migration, and differentiation of epicardial and epicardially-derived cells
	exerts an important, yet previously unappreciated function in regulating H3K27 histone modifications and repressing gene expression
	regulates epicardial EMT and heart development through canonical WNT, non-canonical WNT, and retinoic acid signaling pathways
	main role in the regulation of the process of Mesenchimal-Epithelial-Transition and in the development and maturation of podocytes
	in prostate cancer WT1 may function as a novel oncogene facilitating development of the lethal metastatic phenotype
	implicated both in normal developmental processes and in the generation of a variety of solid tumors and hematological malignancies
	is a regulator of the mitotic checkpoint and chromosomal stability
	central role of WT1 in podocyte differentiation

CELLULAR PROCESS	cell life, differentiation
	cell life, proliferation/growth
	nucleotide, transcription, regulation

PHYSIOLOGICAL PROCESS

development

text	normal kidney differentiation, hemapoietic progenitor cells ; involved in nephrogenesis

PATHWAY

metabolism

signaling

	role of CITED2 during sex determination through a WT1/NR5A1 regulatory pathway
	biological function of menin-WT1 regulated PAX2 signaling in endocrine neoplasia and renal disease

a component

INTERACTION

DNA	binding to both GC-rich and TC repeat elements that are present in multiple promoters

RNA

small molecule

protein	regulating for SRY in the sex determination pathway
	interacting with CITED2, NR5A1
	HTRA2 is a WT1 binding partner that cleaves WT1 at multiple sites following the treatment of cells with cytotoxic drugs
	transcriptional activator of the immunosuppressant cytokine interleukin-10 (IL10)
	BASP1 is a WT1 cofactor that suppresses the transcriptional activation function of WT1
	ALDH1A2 is a direct transcriptional target of WT1 in epicardial cells
	MEN1 specifically interact with WT1 (WT1 is a specific cofactor for menin-dependent and PcG-mediated H3K27 trimethylation and DNA hypermethylation for gene silencing)
	LIMS1 interacted with WT1, a nuclear transcription factor that is essential for regulating podocyte-specific gene expression in adult kidney
	VEGFA is a direct, bona fide WT1 target gene in sarcoma and WT1 plays a key role in optimizing the response of tumor cells to hypoxia
	bound to the SRPK1 promoter, and repressed expression through a specific WT1 binding site
	SOX11 represents a synergistic factor for WT1 in regulating the WNT4 gene expression that is critical for nephrogenesis during kidney ontogeny
	NR2F2 directly regulates the expression of both EYA1 and WT1 in the metanephric mesenchyme
	BASP1 interacts with WT1 and converts WT1 from a transcriptional activator to a repressor
	USP18 is a transcriptional target of WT1, suggesting that increased expression of USP18 following WT1 loss contributes to Wilms tumorigenesis
	maintains testicular cord integrity by regulating the expression of COL4A1 and COL4A2
	ZNF224, is a novel WT1-associating protein that enhances the transcriptional activation of the human vitamin D receptor promoter by WT1
	WT1 regulates the mitotic checkpoint complex (MCC) by directly interacting with the spindle assembly checkpoint protein, MAD2L1
	NR4A1 protects pancreatic beta-cells against H2O2 mediated apoptosis by up-regulating WT1 expression

cell & other

promoting quiescence of the CD34(+), CD38(-), stem cell population

REGULATION

inhibited by

phosphorylation by PKA, resulting in its translocation from nucleus to cytosol

Other

regulated by EP300 (increased the expression of endogenous WT1 mRNA and promoted the activation of the WT1 promoter and intronic enhancer)

ASSOCIATED DISORDERS

corresponding disease(s)

DDS , FS , IDMS , GUD , WAGR , SRN4 , NPHS4

related resource

Wilms Tumour database

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral     --over   in myelodysplastic syndrome in progression and in acute leukemia constitutional     --low   in glomerulonephritis or mesanglial scelerosis tumoral   translocation     with EWSR1 t(11;22) (p13;q12) in desmoplastic round-cell tumor constitutional germinal mutation       in renal failure tumoral     --over   in breast cancer with poor prognosis constitutional germinal mutation       in exons 8 and 9 in steroid-resistant nephrotic syndrome tumoral       loss of function in WILMS tumor constitutional         association with congenital diaphragmatic hernia (see DDS) tumoral     --over   in pediatric acute myeloid leukemia but does not predict survival constitutional     --low   in Sertoli cells results in the downregulation of the important basal lamina component, which in turn, causes the breakdown of the basal lamina and subsequent testicular cord disruption

Susceptibility

to Wilms tumor susceptibility to tuberculosis

Variant & Polymorphism SNP	rs2057178 SNP associated with susceptibility to tuberculosis

Candidate gene
Marker	EPS8, as ABCB1 and WT1, may be a clinically valuable biomarker for assessing the outcome of acute lymphoblastic leukemia (ALL) patients
Therapy target

ANIMAL & CELL MODELS

mouse strains lacking KTS+isoform, showing a complex XY sex reversal due to a drastic reduction of Sry expression pattern