WT1
protein-codingWT1 transcription factor, the group of Zinc fingers C2H2-type
Gene summary
This gene encodes a transcription factor that contains four zinc-finger motifs at the C-terminus and a proline/glutamine-rich DNA-binding domain at the N-terminus. It has an essential role in the normal development of the urogenital system, and it is mutated in a small subset of patients with Wilms tumor. This gene exhibits complex tissue-specific and polymorphic imprinting pattern, with biallelic, and monoallelic expression from the maternal and paternal alleles in different tissues. Multiple transcript variants have been described. In several variants, there is evidence for the use of a non-AUG (CUG) translation initiation codon upstream of, and in-frame with the first AUG. Authors of PMID:7926762 also provide evidence that WT1 mRNA undergoes RNA editing in human and rat, and that this process is tissue-restricted and developmentally regulated. [provided by RefSeq, Mar 2015]
- GUD
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~47.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0007635
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0019006
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0008679
Submitter: ClinGen
Wilms tumor is the most common renal tumor of childhood, occurring with an incidence of 1 in 10,000 and with a median age of diagnosis between 3 and 4 years of age. Wilms tumours are thought to develop from abnormally persistent embryonal cells within nephrogenic rests (PMID: 19948536). The WT1 gene encodes a zinc finger DNA-binding protein that acts as a transcriptional activator or repressor depending on the cellular or chromosomal context (PMID: 1127846). The relationship between WT1 and Wilms tumor type 1 (autosomal dominant) was first reported in 1991 (Pelletier et al., PMID: 1654525). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Seven variants (nonsense, frameshift) in this gene reported in at least 8 probands in 3 publications (PMIDs: 15483024, 1654525, 18688870) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is also supported by expression studies, cell culture and mouse models (PMIDs: 2164159, 26035382, 21123950, 14645201). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in molecular mechanism and phenotypic variability between Wilms tumor type 1 and congenital malformation syndromes associated with WT1 variants (Denys-Drash syndrome, Frasier syndrome, Meacham syndrome, and nephrotic syndrome, type 4). For example, many individuals with Denys-Drash syndrome harbor heterozygous missense variants in exon 8 or 9 and may act in a dominant-negative manner (Royer-Pokora et al., 2004; PMID: 15150775), while the majority of variants reported for Wilms tumor type 1 are loss-of-function variants. Therefore, we have split curations for WT1 into Wilms tumor type 1 and congenital malformation syndromes associated with variants in WT1. In summary, loss of function variants in WT1 are definitively associated with autosomal dominant Wilms tumor type 1. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Inheritance Pattern: AD
Disease ID:MONDO:0008679
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0008682
Submitter: ClinGen
WT1 associated congenital malformation syndromes include Denys-Drash syndrome (DDS), Frasier syndrome, Meacham syndrome, and nephrotic syndrome, type 4. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found that these congenital malformation syndromes have similar or overlapping clinical features and share a postulated dominant-negative mechanism. Therefore, we have lumped curations of these congenital malformation syndromes associated with WT1 into DDS, in which they are part of a spectrum and not distinct conditions although Wilms Tumor is more frequent in DDS than in Frasier syndrome. Of note, the WT1 gene has also been implicated in Wilms tumor type 1 which results from loss of function variants and a high risk of Wilms Tumor and was curated separately. WT1 is composed of ten exons and encodes a protein with four zinc-finger motifs with both transcriptional and tumor suppressor activities. WT1 was first reported in 10 patients affected by Denys-Drash syndrome in 1991, where heterozygous constitutional variants in WT1 were found in all tested affected individuals (PMID: 1655284). Variants in the WT1 gene have been identified in >95% of DDS patients (PMID: 1655284). The most commonly seen WT1 variant in DDS is the missense variant WT1 R394W, which is critical for interaction with a guanine in the DNA target. An alternative splice site in intron 9 allows the addition of 3 amino acids (KTS) between the third and fourth zinc fingers of the WT1 protein, resulting in the so-called +KTS isoform. Patients with Frasier syndrome specifically have unique variants in the donor splice site of intron 9 of the WT1 gene with a predicted loss of the +KTS isoform (PMID:9398852). Nine probands with DDS in four publications are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease association is also supported by mouse models, biochemical function and functional alteration studies (PMID:11278460, 1655284, 10077614, 15509792). In summary, WT1 is definitively associated with the autosomal-dominant (AD) Denys-Drash syndrome, Frasier syndrome and related disorders. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.
Inheritance Pattern: AD
Disease ID:MONDO:0008679
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0008682
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Endocrine; Genitourinary; Oncologic; Renal; Pulmonary
Intervention: Cardiovascular; Oncologic; Renal
Rationale: Individuals are at risk for several types of neoplasm, and surveillance may allow early detection and treatment for common oncologic features (eg, Wilms tumor, gonadoblastoma); Renal transplant may be indicated (and beneficial) in individuals with end-stage renal faiure; Meacham syndrome can involve congenital cardiac anomalies, and awareness may allow early management
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to WT1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_024426.6. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 2 | 13 | 501 | 5 | 521 | |
| missense | 17 | 47 | 922 | 93 | 2 | 1081 |
| nonsense | 28 | 14 | 9 | 51 | ||
| start loss | 0 | |||||
| frameshift | 41 | 20 | 13 | 74 | ||
| splice donor/acceptor (+/-2bp) | 4 | 12 | 10 | 26 | ||
| Total | 90 | 95 | 967 | 594 | 7 | 1753 |
Highest pathogenic variant AF is 0.00005634207
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_077744.4 | 10 | MANE Select | |
| Ensembl | ENSP00000415516.5 | 10 | MANE Select | |
| RefSeq | NP_000369.4 | 9 | Standard | |
| RefSeq | NP_001185480.1 | 10 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| wt1a | Danio rerio | Structure: podocyte Quality: flattened abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Transcriptional misregulation in cancer - Homo sapiens (human)
- Primary Focal Segmental Glomerulosclerosis FSGS
- chaperones modulate interferon signaling pathway
- overview of telomerase protein component gene htert transcriptional regulation
- p73 transcription factor network
Biological Process
- negative regulation of transcription by RNA polymerase II
- vasculogenesis
- ureteric bud development
- branching involved in ureteric bud morphogenesis
- kidney development
Molecular Function
- DNA-binding transcription factor activity, RNA polymerase II-specific
- DNA-binding transcription activator activity, RNA polymerase II-specific
- DNA-binding transcription factor activity
- RNA binding
- protein binding
Cellular Component
- nucleus
- nucleoplasm
- nucleolus
- cytoplasm
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000332351
- Coding exons
- 10
- Length
- 47856
- Individuals with no LoFs
- 125743
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 5
- Defined
- 125748
- p
- 0.0000199
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.78 | 201 | 286 | 0.704 | 0.0000155 | 3341 |
| Missense (PolyPhen) | 72 | 127.08 | 0.56659 | 1496 | ||
| Synonymous | -0.0334 | 120 | 120 | 1.00 | 0.00000649 | 1017 |
| Loss of Function | 4.31 | 2 | 25.5 | 0.0785 | 0.00000139 | 273 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00016 | 0.00011 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.0000088 | 0.0000088 | rare |
| South Asian | 0.000098 | 0.000065 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Transcription factor that plays an important role in cellular development and cell survival (PubMed:7862533). Recognizes and binds to the DNA sequence 5'-GCG(T/G)GGGCG-3' (PubMed:7862533, PubMed:17716689, PubMed:25258363). Regulates the expression of numerous target genes, including EPO. Plays an essential role for development of the urogenital system. It has a tumor suppressor as well as an oncogenic role in tumor formation. Function may be isoform-specific: isoforms lacking the KTS motif may act as transcription factors (PubMed:15520190). Isoforms containing the KTS motif may bind mRNA and play a role in mRNA metabolism or splicing (PubMed:16934801). Isoform 1 has lower affinity for DNA, and can bind RNA (PubMed:19123921). {ECO:0000269|PubMed:15520190, ECO:0000269|PubMed:16934801, ECO:0000269|PubMed:17716689, ECO:0000269|PubMed:19123921, ECO:0000269|PubMed:19416806, ECO:0000269|PubMed:25258363, ECO:0000269|PubMed:7862533}.;
- Disease
- DISEASE: Frasier syndrome (FS) [MIM:136680]: Characterized by a slowly progressing nephropathy leading to renal failure in adolescence or early adulthood, male pseudohermaphroditism, and no Wilms tumor. As for histological findings of the kidneys, focal glomerular sclerosis is often observed. There is phenotypic overlap with Denys-Drash syndrome. Inheritance is autosomal dominant. {ECO:0000269|PubMed:10571943}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Wilms tumor 1 (WT1) [MIM:194070]: Embryonal malignancy of the kidney that affects approximately 1 in 10'000 infants and young children. It occurs both in sporadic and hereditary forms. {ECO:0000269|PubMed:1317572, ECO:0000269|PubMed:15150775, ECO:0000269|PubMed:9108089, ECO:0000269|PubMed:9529364}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Denys-Drash syndrome (DDS) [MIM:194080]: Typical nephropathy characterized by diffuse mesangial sclerosis, genital abnormalities, and/or Wilms tumor. There is phenotypic overlap with WAGR syndrome and Frasier syndrome. Inheritance is autosomal dominant, but most cases are sporadic. {ECO:0000269|PubMed:10738002, ECO:0000269|PubMed:10799199, ECO:0000269|PubMed:11182928, ECO:0000269|PubMed:11519891, ECO:0000269|PubMed:1302008, ECO:0000269|PubMed:1338906, ECO:0000269|PubMed:15349765, ECO:0000269|PubMed:1655284, ECO:0000269|PubMed:8111391, ECO:0000269|PubMed:8112732, ECO:0000269|PubMed:8295405, ECO:0000269|PubMed:8388765, ECO:0000269|PubMed:8411073, ECO:0000269|PubMed:8741319, ECO:0000269|PubMed:8956030, ECO:0000269|PubMed:9475094, ECO:0000269|PubMed:9529364}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Nephrotic syndrome 4 (NPHS4) [MIM:256370]: A form of nephrotic syndrome, a renal disease clinically characterized by severe proteinuria, resulting in complications such as hypoalbuminemia, hyperlipidemia and edema. Kidney biopsies show non-specific histologic changes such as focal segmental glomerulosclerosis and diffuse mesangial proliferation. Some affected individuals have an inherited steroid-resistant form and progress to end-stage renal failure. Most patients with NPHS4 show diffuse mesangial sclerosis on renal biopsy, which is a pathologic entity characterized by mesangial matrix expansion with no mesangial hypercellularity, hypertrophy of the podocytes, vacuolized podocytes, thickened basement membranes, and diminished patency of the capillary lumen. {ECO:0000269|PubMed:11182928, ECO:0000269|PubMed:15253707, ECO:0000269|PubMed:20798252, ECO:0000269|PubMed:9529364, ECO:0000269|PubMed:9607189}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Meacham syndrome (MEACHS) [MIM:608978]: Rare sporadically occurring multiple malformation syndrome characterized by male pseudohermaphroditism with abnormal internal female genitalia comprising a uterus and double or septate vagina, complex congenital heart defect and diaphragmatic abnormalities. {ECO:0000269|PubMed:17853480}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=A chromosomal aberration involving WT1 may be a cause of desmoplastic small round cell tumor (DSRCT). Translocation t(11;22)(p13;q12) with EWSR1.; DISEASE: Mesothelioma, malignant (MESOM) [MIM:156240]: An aggressive neoplasm of the serosal lining of the chest. It appears as broad sheets of cells, with some regions containing spindle- shaped, sarcoma-like cells and other regions showing adenomatous patterns. Pleural mesotheliomas have been linked to exposure to asbestos. {ECO:0000269|PubMed:8401592}. Note=The disease may be caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.875
Intolerance Scores
- RVIS EVS
- -0.45
- RVIS percentile EVS
- 24
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.991
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |