Scientific background:

Summary: 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: 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.

Molecule: 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.

Pathophysiology: 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.

Clinical signs: 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.  » » » 
   

Methodology:

	clinical test	Method		Genomic sequencing of the entire coding region
		Turn-around time		15 working days
		Effort		little
		Specimen		DNA
		Quality assessment		Internal quality control only
	All known and new missense, nonsense and splice mutations can be detected.
	clinical test	Method		Multiplex Ligation-Dependent Probe Amplification
		Turn-around time		25 working days
		Effort		little
		Specimen		DNA
		Quality assessment		Internal quality control only
	clinical test	Method		Carrier testing
		Turn-around time		5 working days
		Effort		little
		Specimen		DNA
		Quality assessment		Internal quality control only
	The test is only specific about the mutation already known in this kindred.

Literature: 

Ito S et al. (2003) Alport syndrome-like basement membrane changes in Frasier syndrome: an electron microscopy study.
Ohtaka A et al. (2002) Phenotypic change of glomerular podocytes in primary focal segmental glomerulosclerosis: developmental paradigm?
Ito S et al. (2001) Isolated diffuse mesangial sclerosis and Wilms tumor suppressor gene.
Takata A et al. (2000) Constitutional WT1 correlate with clinical features in children with progressive nephropathy.
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.
Mendelsohn HB et al. (1982) Familial early-onset nephrotic syndrome: diffuse mesangial sclerosis. Clinico-pathological study of a kindred.