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      46,XY Phenotypic Male with Focal Segmental Glomerulosclerosis Caused by the WT1 Splice Site Mutation

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          Objective: Frasier syndrome is characterized by progressive glomerulopathy due to nonspecific focal and segmental glomerulosclerosis (FSGS), 46,XY sex reversal and the development of gonadoblastoma from dysgenetic gonads. Donor splice site heterozygous mutations in intron 9 of the Wilms’ tumor gene (WT1) cause this disease. We investigated whether WT1 mutations showed clinical heterogeneity. Patients and Methods: A 6-year-old phenotypic boy was diagnosed as having FSGS. His karyotype was 46,XY. Gonadotropin-releasing hormone and human chorionic gonadotropin stimulation tests revealed normal luteinizing hormone, follicle-stimulating hormone and testosterone responses. The other patient was a 7-year-old 46,XY female with FSGS. Prophylactic gonadectomy was performed and gonadoblastoma was found. By polymerase chain reaction and direct sequencing, WT1 was analyzed in these patients. Results and Conclusion: Both patients had IVS9 + 5G→A in intron 9 of the WT1. Our study indicates a normal 46,XY phenotypic male patient with FSGS. The phenotypic variations of the WT1 splice site mutations are further expanded.

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

          Denys-Drash syndrome is a rare human condition in which severe urogenital aberrations result in renal failure, pseudohermaphroditism, and Wilms' tumor (nephroblastoma). To investigate its possible role, we have analyzed the coding exons of the Wilms' tumor suppressor gene (WT1) for germline mutations. In ten independent cases of Denys-Drash syndrome, point mutations in the zinc finger domains of one WT1 gene copy were found. Nine of these mutations are found within exon 9 (zinc finger III); the remaining mutation is in exon 8 (zinc finger II). These mutations directly affect DNA sequence recognition. In two families analyzed, the mutations were shown to arise de novo. Wilms' tumors from three individuals and one juvenile granulosa cell tumor demonstrate reduction to homozygosity for the mutated WT1 allele. Our results provide evidence of a direct role for WT1 in Denys-Drash syndrome and thus urogenital system development.
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            Donor splice-site mutations in WT1 are responsible for Frasier syndrome.

            Frasier syndrome (FS) is a rare disease defined by male pseudo-hermaphroditism and progressive glomerulopathy. Patients present with normal female external genitalia, streak gonads and XY karyotype and frequently develop gonadoblastoma. 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 adulthood. No case of Wilms' tumour has been reported, even in patients with extended follow-up. In contrast with FS patients, most individuals with Denys-Drash syndrome (DDS; 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' tumour. Mutations of the Wilms'-tumour gene, WT1, cause different pathologies of the urogenital system, including DDS. WT1 is composed of ten exons and encodes a protein with four zinc-finger motifs and transcriptional and tumour-suppressor activities. 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.
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              Spectrum of early onset nephrotic syndrome associated with WT1 missense mutations.

              We investigated 17 children with nephrotic syndrome (NS) of early onset (14 aged < 1 year) and rapid progression to end-stage renal disease for the presence of mutations in the Wilms' tumor suppressor gene WT1 on chromosome 11. In eight children (7 genotypic males) an association with Wilms' tumor and/or ambiguous genitalia (Denys-Drash syndrome) was observed. In these eight and two additional female patients with NS only constitutional missense mutations in the WT1 gene were detected; four children presented the so-called hot spot mutation in exon 9 (R394N) and six had different mutations in exons 8 and 9 (4 not previously described). Renal biopsy showed diffuse mesangial sclerosis in eight and focal segmental sclerosis in two cases. End-stage renal disease was reached either concomitantly or within four months after onset of NS in seven of ten patients. A unilateral Wilms' tumor was found before or concomitant with NS in four children (3 males, 1 female). From the seven genotypic males with WT1 mutations, five presented ambiguous genitalia and two a female phenotype. No mutation of the WT1 gene was found in seven other children with isolated congenital or infantile NS with or without DMS who appeared to have a slower progression than the first group. It is proposed that patients with early onset, rapidly progressive NS and diffuse mesangial or focal segmental sclerosis should be tested for WT1 mutations to identify those at risk for developing Wilms' tumor.

                Author and article information

                Horm Res Paediatr
                Hormone Research in Paediatrics
                S. Karger AG
                28 November 2003
                : 60
                : 6
                : 302-305
                Departments of aPediatrics, bFirst Pathology, and cUrology, Hokkaido University School of Medicine, dDepartment of Pediatrics, Teine Keijin-kai Hospital, Sapporo, eDepartment of Pediatrics, Kushiro Red Cross Hospital, Kushiro, Japan
                74249 Horm Res 2003;60:302–305
                © 2003 S. Karger AG, Basel

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                Figures: 2, References: 20, Pages: 4
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