Alternative splicing of WT1 generates 4 isoforms: the fifth exon may or may not be present, and an alternative splice site in intron 9 allows the addition of 3 amino acids (lys-thr-ser, or KTS) between the third and fourth zinc fingers of the WT1 protein (Haber et al., 1991). In 3 unrelated patients with Frasier syndrome (136680), Barbaux et al. (1997) identified a mutation in the donor splice site in intron 9 of WT1, with the predicted loss of the so-called +KTS isoform. Examination of WT1 transcripts showed a diminution of the +KTS/-KTS isoform ratio in patients with Frasier syndrome. Two of 3 patients were found to carry a C-to-T transition at position +4 of intron 9 in 1 allele (IVSDS+4C-T). This nucleotide substitution was not detected in the DNA from either parent, indicating a de novo mutation. A third patient was found to have a mutation in intron 9 at position +6, substituting a thymidine for an adenine (IVS9DS+6A-T; 607102.0019). A screen of the SRY gene (480000) had failed to detect mutations in any of the 3 patients.
Klamt et al. (1998) reported 3 cases of Frasier syndrome and the IVS9DS+4C-T mutation.
Barbosa et al. (1999) stated that 18 patients with Frasier syndrome had been described, all with heterozygous point mutations affecting the donor splice site of intron 9 of WT1; none had presented with Wilms tumor. They described 2 patients with Frasier syndrome and the IVS9DS+4C-T mutation; one of these patients also had Wilms tumor. The mutation was detected in both peripheral blood and in tumor-derived DNA of the patient with Frasier syndrome and Wilms tumor. The congenital anomalies in these 2 patients were the same as in other cases of Frasier syndrome: female external genitalia, in spite of a 46,XY karyotype, and streak gonads. The nephroblastoma in the patient with Wilms tumor had been diagnosed at the age of 3 years. The possibility that the patient actually represented a case of Denys-Drash syndrome was rejected because of normal histology of the kidney removed at age 3; the late onset of proteinuria; the slow progression of nephropathy, once developed; and the presence of a complete female phenotype with dysgenetic gonads, typical of Frasier syndrome. Thus this is the only one of 20 patients carrying mutations within splice site 2 of exon 9 of the WT1 gene who developed Wilms tumor in association with the features of Frasier syndrome.
Melo et al. (2002) reported a 19-year-old male with Frasier syndrome who had the IVS9+4C-T mutation, which predicts a change in splice site utilization. He had an unusual phenotype. WT1 transcript analysis showed reversal of the normal positive/negative KTS isoform ratio, confirming the diagnosis of FS. The authors concluded that this patient had the external genitalia characteristic of Denys-Drash syndrome, suggesting that these 2 syndromes are not distinct diseases but may represent 2 ends of a spectrum of disorders caused by alterations in the WT1 gene.
In a 46,XX female with nephrotic syndrome (NPHS4; 256370), Jeanpierre et al. (1998) identified the IVS9+4C-T mutation in the WT1 gene.
