Laboratory for Molecular Diagnostics
Center for Nephrology and Metabolic Disorders

Wilms tumor 1 gene

WT1 is a zinc finger transcription factor, which acts as activator or repressor depending on the developmental or cellular context. Mutations of the gene result in disturbed genital development, Wilms tumour, and mesangial sclerosis.

Gene Structure

Four splice variants containing 10 and 9 exons have been identified. It may become more as upstream in in-frame with the first AUG, there is evidence of an other non-AUG (CUG) translation initiation site.

The promotor is GC-rich but does not contain a TATA box. SP1 binding sites have been identified and functionally confirmed. The promotor is probably used by an other gene, WIT1, that is transcribed in the opposite direction.

The mRNA is subject to tissue-restricted and developmentally regulated editing, which allows further fine tuning of cellular regulation processes.

Protein Structure

The funtioning transcription factor consists of four zinc-finger motifs at the C-terminus and a proline/glutamine-rich DNA-binding domain at the N-terminus.

Phenotype

Somatic mutations of the WT1 gene have been observed in a small number of Wilms tumors. Also, familial Wilms tumors are associated with heterozygous germline mutations, but most of these tumors an additional somatic mutation of the gene has been identified, indicating a second hit.

The WAGR syndrome was the first congenital disorder associated with this gene. The condition described by the features Wilms tumor, aniridia, urogenital malformations, and mental retardation is caused by truncating mutations often involving the downstream neighbor, the PAX6 gene.

Gene Regulation

The gene product, a zinc-finger transcription factor, controls normal development of the urogenital system. In podocytes it is essential to differentiation that includes the formation of a normal slit diaphragm.

Genetests:

Clinic Method Carrier testing
Turnaround 5
Specimen type genomic DNA
Clinic Method Multiplex Ligation-Dependent Probe Amplification
Turnaround 20
Specimen type genomic DNA
Clinic Method Genomic sequencing of the entire coding region
Turnaround 15
Specimen type genomic DNA
Clinic Method Massive parallel sequencing
Turnaround 25
Specimen type genomic DNA

Related Diseases:

Congenital nephrotic syndrome type 04
WT1
WAGR syndrome
PAX6
WT1
Denys-Drash syndrome
WT1
Frasier syndrome
WT1
Aniridia-Wilms-tumor syndrome
PAX6
WT1
Somatic nephroblastoma
GPC3
WT1

References:

1.

Takata A et al. (2000) Constitutional WT1 correlate with clinical features in children with progressive nephropathy.

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2.

Ito S et al. (2001) Isolated diffuse mesangial sclerosis and Wilms tumor suppressor gene.

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3.

Ohtaka A et al. (2002) Phenotypic change of glomerular podocytes in primary focal segmental glomerulosclerosis: developmental paradigm?

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4.

Ito S et al. (2003) Alport syndrome-like basement membrane changes in Frasier syndrome: an electron microscopy study.

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5.

Mendelsohn HB et al. (1982) Familial early-onset nephrotic syndrome: diffuse mesangial sclerosis. Clinico-pathological study of a kindred.

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6.

Jeanpierre C et al. (1998) Identification of constitutional WT1 mutations, in patients with isolated diffuse mesangial sclerosis, and analysis of genotype/phenotype correlations by use of a computerized mutation database.

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Update: Sept. 26, 2018