1/5. Novel WT1 mutation (C388Y) in a female child with denys-drash syndrome.We report the identification of a novel wilms tumor suppressor gene mutation in a 5-month-old girl who presented with unilateral wilms tumor (WT) and renal diffuse mesangial sclerosis typical of denys-drash syndrome (DDS). The patient did not have ambiguous genitalia and the karyotype (by amniocentesis) was 46, XX. A de novo constitutional heterozygous mutation in WT1 gene exon 9 coding for the third zinc-finger (1163G-->A, C388Y) was identified. This mutation affects a cysteine residue involved in the coordination of the zinc atom, confirming the importance of these residues in the biological function of WT1 protein.- - - - - - - - - - ranking = 1keywords = karyotype (Clic here for more details about this article) |
2/5. Molecular analysis of frasier syndrome: mutation in the WT1 gene in a girl with gonadal dysgenesis and nephronophthisis.The Wilms' tumor gene (WT1) encodes a protein that is believed to exert transcriptional and tumor-suppressor activities. Mutations in this gene have occasionally been associated with Wilms' tumor (<15% patients) and, more consistently, with three syndromes characterized by urogenital abnormalities (WAGR, Denys-Drash and Frasier syndromes). We report 17 years follow-up of a 29 year-old phenotypic female with 46,XY karyotype, gonadal dysgenesis and nephronophthisis in order to identify possible germline alterations of the WT1 gene. frasier syndrome was suspected and confirmed by genetic analysis. Sequence analysis permitted the identification of an A40-->G mutation in position 5 in the donor splice site of intron 9. During surgery for streak gonads extirpation, a microscopic gonadoblastoma was found, a typical complication of frasier syndrome.- - - - - - - - - - ranking = 1keywords = karyotype (Clic here for more details about this article) |
3/5. WT1 gene mutation responsible for male sex reversal and renal failure: the frasier syndrome.We report the case of a young woman with primary amenorrhea. In her childhood, she suffered from renal failure requesting kidney transplantation at the age of 11. The investigations for primary amenorrhea revealed a hypergonadotropic hypogonadism associated with 46 XY karyotype. The association of primary amenorrhea with renal failure suggested frasier syndrome (FS) or denys-drash syndrome (DDS). Genetic analysis revealed a Wilms' tumour (WT1) gene mutation characteristic of the frasier syndrome. Dysgenetic ovaries were removed laparoscopically due to the risk of gonadal cancer.- - - - - - - - - - ranking = 1keywords = karyotype (Clic here for more details about this article) |
4/5. 46,XY phenotypic male with focal segmental glomerulosclerosis caused by the WT1 splice site mutation.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.- - - - - - - - - - ranking = 1keywords = karyotype (Clic here for more details about this article) |
5/5. A WT1 exon 1 mutation in a child diagnosed with denys-drash syndrome.denys-drash syndrome (DDS) is characterized by nephropathy, genital abnormalities, and predisposition to wilms tumor. DDS is associated with constitutional WT1 mutations, the majority being missense mutations in the zinc-finger region. A dominant-negative mode of action of the mutant DDS proteins is thought to explain the more severe genitourinary phenotype seen in DDS compared with children with complete deletion of one WT1 allele. We present a phenotypically female child who presented with bilateral wilms tumor at 8 months of age. She was found to have an XY karyotype and diagnosed with DDS. In the constitutional dna of this child we found a previously unreported mutation in exon 1 of WT1. This de novo mutation, delT in codon 40, is predicted to produce a termination signal in codon 90 (F40fsX90). This frameshift mutation results in a severely truncated protein, which would remove both the zinc-finger dna-binding domain and the majority of the N-terminal regulatory domain, including regions previously shown in vitro to be necessary for inhibition of WT1 transcriptional activity. Our results provide important physiological evidence that the first 40 amino acids of WT1 are capable of functionally important interactions, presumably through their ability to self-associate with full-length WT1.- - - - - - - - - - ranking = 1keywords = karyotype (Clic here for more details about this article) |