The same mutation affecting the splicing of WT1 gene is present on Frasier syndrome patients with or without Wilms' tumor

Abstract

Denys-Drash and Frasier syndromes are rare human disorders that associate nephropathy with gonadal and genital abnormalities. In DDS there is a predisposition to Wilms' tumor. Heterozygous point mutations in the Wilms' tumor, type1 gene (WT1), particularly those altering the zinc finger (ZF) encoding exons, have been reported in most DDS patients, while mutations in intron 9 of the same gene cause FS. This paper describes two cases of DDS, one FS and one patient with Wilm's tumor and intersex genitalia, in which mutations were searched by sequencing the exons 8 and 9 of WT1 gene. Patient 1 carried a missense point mutation in exon 8 (ZF2), converting a CGA-Arg codon to a TGA-stop codon. Patient 2 presented a single nucleotide deletion within exon 9 (ZF3) introducing a premature chain termination at codon 398. Patients 3 and 4 had a C-->T transition at position +4 of the second alternative splice donor site of exon 9 (this mutation was detected in peripheral blood and in tumor derived DNA of patient 3). However, patient 3 had previously developed a Wilms' tumor. This is the first case of Wilms' tumor development in a phenotypically and genetically confirmed case of FS.

Genotype/Phenotype Correlation in Nephrotic Syndrome Caused by WT1 Mutations

“…(2) None of the NS patients with KTS mutations developed WT. One previous report described a patient with a KTS mutation and FS associated with WT, but our data suggest that this association is an exception (22). (3) In NS patients with KTS mutations: If phenotypic female gender and karyotype were in concordance, patients developed isolated NS only.…”

Frasier syndrome: four new cases with unusual presentations

“…Glomerular symptoms in FS patients consist on childhood proteinuria and nephrotic syndrome (NS), characterized by focal and segmental glomerular sclerosis (FSGS). Patients are frequently unresponsive to treatment with steroids and immunosuppressors, and progress to end-stage renal failure in adolescence or early adulthood (3,4 (7). Different mutations in the Wilms' tumor suppressor gene (WT1, OMIM *607102) located in 11p23 may cause either DDS or FS.…”

WT1 in disease: shifting the epithelial–mesenchymal balance

“…End-stage renal disease is usually reached by adolescence or early adulthood. The risk of Wilms' tumour is much less than in DDS [72,73]. As discussed before, the WT1 KTS splice variation is conserved across all vertebrates [74], and transgenic mice unable to express the different isoforms exhibit differing renal phenotypes, with homozygous animals dying shortly after birth [10].…”