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.
Analysis of exons 2-10 of the WT1 gene in constitutional DNA from five patients with DDS was carried out using the polymerase chain reaction (PCR) and direct DNA sequencing.
The WT1 gene is normally expressed during gonadal development and specific mutations in heterozygous form cause Drash syndrome, characterized by male pseudohermaphroditism and gonadal dysgenesis, renal failure and a predisposition for Wilms' tumour.
Mutations in the donor splice site in intron 9 of the Wilms' tumor (WT1) gene have been shown to cause Frasier syndrome and are distinct from WT1 exon mutations associated with Denys-Drash syndrome.
The decision to do prophylactic nephrectomies was based on the genetic identification of WT1 mutations supporting a diagnosis of incomplete DDS, with the potential for increased risk of malignancy with the development of Wilms' tumour.
The mutations found in our cases occurred in the same exon of the WT1 gene as detected in Denys-Drash syndrome (DDS) and could not be explained by the previously proposed mechanism.
In this report, we describe a family with the well-known missense mutation in exon 9 of the WT1 gene, 1180C>T (R394W), causing incomplete DDS and no symptoms in their father.
Mutations in the WT1 gene causing Wilms tumors were first reported in WAGR syndrome (Wilms tumor, Aniridia, Genitourinary malformation, mental Retardation) and Denys Drash syndrome (pseudohermaphroditism, Wilms tumor, nephropathy), but only in a few patients with hypospadias and cryptorchidism without other signs of Denys Drash (DDS) or WAGR syndrome WT1 mutations were identified.
Analysis of exons 2-10 of the WT1 gene in constitutional DNA from five patients with DDS was carried out using the polymerase chain reaction (PCR) and direct DNA sequencing.
However, in addition to the 12 patients, three DDS patients were also analysed using SSCP, and in all three cases heterozygous WT1 mutations were found which would be predicted to disrupt the DNA binding activity of WT1 protein.
Deletions of the WT1 gene or point mutations which destroy the DNA binding activity of the protein are associated with the development of the pediatric nephroblastoma Wilms tumor and Denys-Drash syndrome.