Donor splice-site mutations in WT1 are responsible for Frasier syndrome
- 1 December 1997
- journal article
- case report
- Published by Springer Science and Business Media LLC in Nature Genetics
- Vol. 17 (4), 467-470
- https://doi.org/10.1038/ng1297-467
Abstract
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.This publication has 27 references indexed in Scilit:
- A clinical overview of WT1 gene mutationsHuman Mutation, 1997
- Dominant negative mutations in the Wilms tumour (WT1) gene cause Denys-Drash syndrome—proof that a tumour-suppressor gene plays a crucial role in normal genitourinary developmentHuman Molecular Genetics, 1992
- Germline mutations in the Wilms' tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndromeCell, 1991
- Clinicopathologic review of twelve children with nephropathy, Wilms tumor, and genital abnormalities (Drash syndrome)The Journal of Pediatrics, 1990
- Nephropathy-Gonadal Dysgenesis, Type 2: Renal Failure in Three Siblings With XY Dysgenesis in OneAmerican Journal of Kidney Diseases, 1987
- Chronic renal failure and XY gonadal dysgenesis: “Frasier” syndrome—a commentary on reported casesAmerican Journal of Medical Genetics, 1987
- A Syndrome of Chronic Renal Failure and XY Gonadal Dysgenesis in Young Phenotypic Females Without Genital AmbiguityAmerican Journal of Kidney Diseases, 1985
- XY gonadal dysgenesis with gonadoblastoma discovered after kidney transplantationAmerican Journal of Obstetrics and Gynecology, 1977
- A syndrome of pseudohermaphroditism, Wilms' tumor, hypertension, and degenerative renal diseaseThe Journal of Pediatrics, 1970
- Gonadoblastoma associated with pure gonadal dysgenesis in monozygous twinsThe Journal of Pediatrics, 1964