/pdf/cancer-incidence-and-survival-among-children-and-adolescents-2w7gert5gr.pdf

Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995.

Germline mutations in the Wilms' tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome.

WILMS' tumour is an embryonic kidney tumour thought to arise through aberrant mesenchymal stem cell differentiation1 and to result from loss of function of a 'tumour suppressor' gene(s)2. Both sporadic and syndrome-associated Wilms' tumours are accompanied by an increased frequency of abnormalities of the urinary tract and genitalia3. Deletional analysis of individuals with the WAGR syndrome4–8 (for, Wilms' tumour, aniridia, genitourinary abnormalities and mental retardation) showed that a Wilms' tumour gene lies at chromosomal position 11p13. This led to the isolation of a candidate Wilms' tumour gene9,10, encoding a zinc-finger protein which is likely to be a transcription factor. To gain insight into the role of this candidate gene in normal development and tumorigenesis, we have now performed in situ messenger RNA hybridization on sections of human embryos and Wilms' tumours. The candidate Wilms' tumour gene is expressed specifically in the condensed mesenchyme, renal vesicle and glomerular epithelium of the developing kidney, in the related mesonephric glomeruli and in cells approximating these structures in tumours. The other main sites of expression are the genital ridge, fetal gonad and mesothelium. These data suggest that (1) this candidate is indeed a Wilms' tumour gene, (2) the associated genital abnormalities are pleiotropic effects of mutation in the Wilms' tumour gene itself, in support of recent genetic analysis11, and (3) this gene has a specific role in kidney development and a wider role in mesenchymal–epithelial transitions.

The candidate Wilms' tumour gene is involved in genitourinary development

Frasier syndrome (FS) is a rare disease defined by male pseudo-hermaphroditism and progressive glomerulopathy1–3. Patients present with normal female external genitalia, streak gonads and XY karyotype4 and frequently develop gonadoblastoma1,2,5,6. Glomerular symptoms consist of childhood proteinuria and nephrotic syndrome, characterized by unspecific focal and segmental glomerular sclerosis, progressing to end-stage renal failure in adolescence or early adulthood4. No case of Wilms′ tumour has been reported, even in patients with extended follow-up1–5. In contrast with FS patients, most individuals with Denys-Drash syndrome (DOS; refs 6,7) have ambiguous genitalia or a female phenotype, an XY karyotype and dysgenetic gonads. Renal symptoms are characterized by diffuse mesangial sclerosis, usually before the age of one year, and patients frequently develop Wilms′ tumour8–9. Mutations of the Wilms′-tumour gene, WT1, cause different pathologies of the urogenital system, including DDS10–12. WT1 is composed of ten exons and encodes a protein with four zinc-finger motifs and transcriptional and tumoursuppressor activities13–15. Alternative splicing generates four isoforms: the fifth exon may or may not be present, and an alternative splice site in intron 9 allows the addition of three amino acids (KTS) between the third and fourth zinc fingers of WT1 (ref. 17). Here we demonstrate that FS is caused by mutations in the donor splice site in intron 9 of WT1, with the predicted loss of the +KTS isoform. Examination of WT1 transcripts indeed showed a diminution of the +KTS/-KTS isoform ratio in patients with FS.

Donor splice-site mutations in WT1 are responsible for Frasier syndrome.

This review summarizes recent advances in our knowledge of the glomerular filter and the causes of hereditary proteinuria syndromes

William H. Hartmann

Papers

A syndrome of pseudohermaphroditism, Wilms' tumor, hypertension, and degenerative renal disease