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WT1
WT1 transcription factor
The WT1 gene provides instructions for a protein essential for the development of the kidneys and gonads, playing a critical role in cell growth, differentiation, and programmed cell death. The WT1 gene is vital for foetal development, particularly in the kidneys and reproductive organs.
WT1 is located on the short (p) arm of chromosome 11, at band 11p13. Arm ratio per GRCh38 - banding schematic.
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Overview
The WT1 gene, also known as WT1 transcription factor, encodes a protein that is fundamental for normal foetal development, specifically influencing the formation of the kidneys and gonads (ovaries and testes). Beyond birth, its activity is largely concentrated in the glomerulus, a crucial filtering structure within the kidneys. The protein derived from the WT1 gene acts as a transcription factor, meaning it regulates the expression of other genes by binding to specific DNA regions.
This regulatory role is important for several cellular processes, including controlling cell growth, guiding cell maturation (differentiation) to perform specialised functions, and initiating apoptosis, which is the body's programmed removal of old or damaged cells. Disruption to the WT1 gene's function can therefore have significant consequences, leading to various developmental conditions and an increased susceptibility to certain cancers, particularly those affecting the kidneys and genitourinary system.
What the gene does
The WT1 protein functions primarily as a transcription factor, which means it regulates the activity of other genes. It achieves this by binding to specific sequences within DNA, thereby controlling gene expression. This regulatory capacity is critical for several fundamental biological processes.
During pre-natal development, the WT1 protein is essential for the proper formation and maturation of the kidneys and the gonads. Its influence extends to coordinating cell growth, ensuring cells mature correctly to perform their specialised roles (differentiation), and managing apoptosis, a process of controlled cell death necessary for normal tissue development and maintenance. After birth, the activity of the WT1 protein becomes more localised, predominantly found in the glomerulus, which is the kidney's blood-filtering unit.
Variants in the WT1 gene can disrupt its ability to bind to DNA, leading to impaired gene regulation. Such disruptions can contribute to conditions like Wilms tumour, where the altered protein may no longer effectively control cell growth or differentiation, potentially leading to uncontrolled cell proliferation.
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Chromosome location
The WT1 gene is situated on chromosome 11, specifically at position 11p13. This location refers to the short (p) arm of chromosome 11, within region 13. The gene spans a significant length of DNA, encoding a protein comprising 449 amino acids.
Protein structure
The WT1 protein consists of 449 amino acids and features several distinct domains and motifs crucial for its function as a transcription factor. An important region is the Disordered (Region) located between amino acids 48-84, which often facilitates protein-protein interactions. The 9aaTAD (Motif) is found at amino acids 236-244, suggesting a role in transcriptional activation.
Central to its DNA-binding capabilities are four C2H2-type zinc finger domains: C2H2-type 1 (amino acids 323-347), C2H2-type 2 (amino acids 353-377), C2H2-type 3 (amino acids 383-405), and C2H2-type 4 (amino acids 414-438). Specific sub-regions within these zinc fingers are Important for interaction with target DNA, such as those at amino acids 367-381 and 393-401. Additionally, a KTS motif is present at amino acids 408-410, which plays a role in alternative splicing and modulating DNA binding specificity.
Key variants
Variants within the WT1 gene can significantly alter the function of the WT1 protein. These genetic changes can range from single base pair substitutions to larger deletions affecting sections of the gene. Pathogenic variants can disrupt the protein's ability to bind DNA, thereby impairing its role in regulating gene expression critical for development and cellular processes. The clinical outcome of a WT1 variant depends on its specific location within the gene and how it affects protein function, potentially leading to developmental disorders, kidney disease, or an increased risk of cancer. Some variants are germline, meaning they are present in all cells of the body and can be inherited, while others are somatic, arising later in life and present only in specific cells, such as tumour cells.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1120C>T | p.Arg374Ter | Pathogenic | ★★☆☆ | WT1-related disorder |
c.1153delinsGG | p.Arg385fs | Pathogenic/Likely pathogenic | ★★☆☆ | Wilms tumor 1 |
c.1303C>T | p.Arg435Ter | Pathogenic | ★★☆☆ | Drash syndrome |
c.1315C>T | p.Arg439Cys | Pathogenic | ★★☆☆ | Frasier syndrome |
c.1316G>A | p.Arg439His | Pathogenic | ★★☆☆ | Drash syndrome |
c.1338C>A | p.His446Gln | Pathogenic | ★★☆☆ | Frasier syndrome |
c.1348C>T | p.His450Tyr | Pathogenic/Likely pathogenic | ★★☆☆ | Nephrotic syndrome, type 4 |
c.1354+2T>C | - | Pathogenic/Likely pathogenic | ★★☆☆ | WT1-related disorder |
c.1372T>C | p.Cys458Arg | Pathogenic | ★★☆☆ | WT1-related disorder |
c.1387C>T | p.Arg463Ter | Pathogenic | ★★☆☆ | Wilms tumor 1 |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the WT1 gene are associated with a spectrum of inherited conditions, predominantly affecting kidney and genitourinary development. These include Denys-Drash syndrome, which typically involves kidney disease, male pseudohermaphroditism, and Wilms tumour, an aggressive kidney cancer that primarily affects children. Familial Wilms tumour is also directly linked to germline WT1 variants. Frasier syndrome, another condition associated with WT1 variants, presents with kidney disease and abnormalities in sexual development. Additionally, Meacham syndrome is associated with WT1 variants and is characterised by severe abnormalities affecting the heart, lungs, and genitourinary system.
Inheritance pattern
Conditions caused by pathogenic WT1 variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
The WT1 gene is included in several Genomic Medicine Service (GMS) approved panels within the UK, indicating its importance in clinical diagnostics. It is assessed in panels for Adult solid tumours cancer susceptibility and Adult solid tumours for rare disease, as well as Childhood solid tumours and Childhood solid tumours cancer susceptibility. Furthermore, WT1 is part of the DDG2P panel, and is included in panels related to Differences in sex development (R146), Embryonal tumour of possible germline origin (R456), Foetal anomalies (R21), Proteinuric renal disease (R195), Unexplained kidney failure in young people, and Wilms tumour with features suggestive of predisposition (R220).
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
Maintaining a healthy lifestyle is generally recommended for overall well-being, though there is no specific evidence to suggest that particular lifestyle modifications can prevent conditions associated with WT1 gene variants. For individuals with a genetic predisposition to Wilms tumour or other kidney conditions due to WT1 variants, general health advice, such as avoiding excessive exposure to environmental toxins and maintaining a balanced diet, may be prudent. Regular medical follow-up, as advised by a healthcare professional, is essential for monitoring and managing any associated health risks.
Supplement considerations
There is no conclusive scientific evidence to support the use of specific dietary supplements in preventing or treating conditions associated with WT1 gene variants. Any individual considering supplements should first consult with a healthcare professional. This is particularly important for those with kidney conditions, as certain supplements may be contraindicated or require dosage adjustments.
Frequently asked questions
What is the primary function of the WT1 gene?
The WT1 gene provides instructions for a protein that acts as a transcription factor, regulating other genes. This protein is essential for the development of the kidneys and gonads before birth, and it plays roles in cell growth, differentiation, and apoptosis.
Which conditions are associated with variants in the WT1 gene?
Variants in the WT1 gene are associated with several conditions, including Wilms tumour, Denys-Drash syndrome, Frasier syndrome, and Meacham syndrome. These conditions primarily affect kidney development, urogenital function, and can increase cancer risk.
Is Wilms tumour always inherited?
No, not always. While some variants in the WT1 gene that cause Wilms tumour are germline and can be inherited, many others are somatic. Somatic variants are acquired during a person's lifetime and are only present in the tumour cells, not in every cell of the body.
How does the WT1 protein regulate gene activity?
The WT1 protein regulates gene activity by binding to specific regions of DNA. This action allows it to control the expression of other genes, influencing processes such as cell growth, maturation (differentiation), and programmed cell death (apoptosis).
Where is the WT1 gene located?
The WT1 gene is located on chromosome 11, specifically at position 11p13. This genomic location is relevant for understanding its role in various genetic conditions.
References
- Deng C, Dai R, Li X. Genetic variation frequencies in Wilms' tumor: A meta-analysis and systematic review. Cancer science. 2016. PMID: 26892980
- Salvatorelli L, Parenti R, Leone G. Wilms tumor 1 (WT1) protein: Diagnostic utility in pediatric tumors. Acta histochemica. 2015. PMID: 25881478
- Al-Hussain T, Ali A, Akhtar M. Wilms tumor: an update. Advances in anatomic pathology. 2014. PMID: 24713986
- Miller-Hodges E, Hohenstein P. WT1 in disease: shifting the epithelial-mesenchymal balance. The Journal of pathology. 2012. PMID: 21959952
- Andrade JG, Guaragna MS, Soardi FC. Clinical and genetic findings of five patients with WT1-related disorders. Arquivos brasileiros de endocrinologia e metabologia. 2008. PMID: 19169475
- Yang L, Han Y, Suarez Saiz F. A tumor suppressor and oncogene: the WT1 story. Leukemia. 2007. PMID: 17361230
- Ariyaratana S, Loeb DM. The role of the Wilms tumour gene (WT1) in normal and malignant haematopoiesis. Expert reviews in molecular medicine. 2007. PMID: 17524167
- Suri M, Kelehan P, O'neill D. WT1 mutations in Meacham syndrome suggest a coelomic mesothelial origin of the cardiac and diaphragmatic malformations. American journal of medical genetics. Part A. 2007. PMID: 17853480
- Heathcott RW, Morison IM, Gubler MC. A review of the phenotypic variation due to the Denys-Drash syndrome-associated germline WT1 mutation R362X. Human mutation. 2002. PMID: 11933209