Role for the Wilms tumor gene in genital development?

Abstract

Detailed molecular definition of the WAGR region at chromosome llpl3 has been achieved by chromosome breakpoint analysis and long-range restriction mapping. Here we describe the molecular detection of a cytogenetically invisible 1-megabase deletion in an individual with aniridia, cryptorchidism, and hypospadias but no Wilms tumor (WT). The region of overlap between this deletion and one associated with WT and similar genital anomalies but no aniridia covers a region of 350-400 kilobases, which is coincident with the extent of homozygous deletion detected in tumor tissue from a sporadic WT. A candidate WT gene located within this region has recently been isolated, suggesting nonpenetrance for tumor expression in the first individual. The inclusion within the overlap region of a gene for WT predisposition and a gene for the best-documented WT-associated genitourinary malformations leads us to suggest that both ofthese anomalies result from a loss-of-function mutation at the same locus. This in turn implies that the WT gene exerts pleiotropic effect on both kidney and genitourinary development, a possibility supported by the observed expression pattern of the WT candidate gene in developing kidney and gonads.Wilms tumor (WT) is a kidney malignancy-the most frequently seen solid tumor of childhood. Most cases are sporadic and unilateral, with no associated anomalies. Bilateral and familial tumors, comprising approximately 7% and 1% of the incidence, respectively (1), have an earlier age of onset than unilateral cases. On the basis of such statistics, the two-hit hypothesis formulated originally for retinoblastoma was extended to WT (2). This model suggests that two mutational steps are required for the development of these childhood tumors. In the hereditary (bilateral and familial) cases, the first predisposing mutation is postulated to be present already in the germ-line and therefore present constitutively in all cells of the target tissue-hence, the earlier age of onset. In sporadic cases, two mutations have to accumulate postzygotically within the same target cell. Ninety-five percent of all WT cases have presented by the age of 10 years (1), suggesting that the target-cell population disappears as development to mature form is completed.Apart from rare familial incidence, the most clear-cut evidence for the presence of a predisposing DNA-level change has come from the unexpectedly frequent association (1 in 100) of WT with aniridia (absence of iris) (3). After this observation, the diagnosis of sporadic aniridia in newborn infants, especially when accompanied by other anomalies, became a prognostic indicator for the possible development of WT. In many such cases, additional genitourinary abnormalities and mental retardation are also present-hence, the acronym WAGR for this syndrome. Karyotypic analysis of WAGR cases revealed the frequent presence of a deletion on one chromosome 11 homolog, always including part of band 11pl3 (4). Only about 60% of the cases with a visible deletion develop WT, demonstra...

Sequence of the WT1 Upstream Region Including the Wit-1 Gene

“…In addition, genitourinary abnormalities such as cryptorchidism and hypospadias can be caused by the inactivation or deletion of one copy of the gene in germline DNA (8,11). A much more severe phenotype of nephropathy, intersex, and a high incidence of Wilms tumors are seen in patients with DenysDrash syndrome, which appears to be due to specific missense mutations within the zinc finger domain of the WTl protein (9).…”

Frasier Syndrome with Childhood-Onset Renal Failure

“…Defects of the WT1 gene account for only a minority (<15%) of Wilms’ tumour (WT) cases [2], but have been demonstrated to cause the WAGR syndrome [3], Denys-Drash syndrome (DDS) [4]and Frasier syndrome (FS) [5]. The WAGR syndrome includes WT, aniridia, genital anomalies and mental retardation.…”

“…WAGR syndrome is caused by constitutional deletion of one copy of the WT1 gene [3]; DDS is caused by heterozygous (dominant negative) mutations of the same gene [4]and FS is determined by heterozygous mutations occurring at an alternative splice site at intron 9 between the regions encoding for the 3rd and 4th zinc finger motifs [9, 10]. …”

Zinc finger point mutations within the WT1 gene in Wilms tumor patients.

“…It was therefore hypothesized that at least some WTs arise due to the loss of function of both copies of a recessive tumor suppressor gene situated at 11p13 (4). Comprehensive mapping of the deletions present in WAGR patients confined the putative gene to a particular 325-kilobase (kb) Not I fragment (5)(6)(7) and indicated that this gene may also be involved with the genital anomalies seen in WAGR patients (8). Two groups (9,10) recently cloned a candidate WT gene from the 11p13 smallest region of overlap.…”