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Molecular and Cellular Biology Jun 2007The Wilms' tumor protein Wt1 plays an essential role in mammalian urogenital development. WT1 mutations in humans lead to a variety of disorders, including Wilms' tumor,...
The Wilms' tumor protein Wt1 plays an essential role in mammalian urogenital development. WT1 mutations in humans lead to a variety of disorders, including Wilms' tumor, a pediatric kidney cancer, as well as Frasier and Denys-Drash syndromes. Phenotypic anomalies in Denys-Drash syndrome include pseudohermaphroditism and sex reversal in extreme cases. We have used cDNA microarray analyses on Wt1 knockout mice to identify Wt1-dependent genes involved in sexual development. The gene most dramatically affected by Wt1 inactivation was Amhr2, encoding the anti-Müllerian hormone (Amh) receptor 2. Amhr2 is an essential factor for the regression of the Müllerian duct in males, and mutations in AMHR2 lead to the persistent Müllerian duct syndrome, a rare form of male pseudohermaphroditism. Here we show that Wt1 and Amhr2 are coexpressed during urogenital development and that the Wt1 protein binds to the promoter region of the Amhr2 gene. Inactivation and overexpression of Wt1 in cell lines was followed by immediate changes of Amhr2 expression. The identification of Amhr2 as a Wt1 target provides new insights into the role of Wt1 in sexual differentiation and indicates, in addition to its function in early gonad development and sex determination, a novel function for Wt1, namely, in Müllerian duct regression.
Topics: Animals; Binding Sites; Cell Line; Chromatin Immunoprecipitation; DNA, Complementary; Genes, Reporter; Genes, Wilms Tumor; Luciferases; Male; Male Urogenital Diseases; Mesonephros; Mice; Mice, Knockout; Models, Genetic; Mullerian Ducts; Mutation; Oligonucleotide Array Sequence Analysis; Promoter Regions, Genetic; Protein Binding; Receptors, Peptide; Receptors, Transforming Growth Factor beta; Sertoli Cells; WT1 Proteins; Wilms Tumor
PubMed: 17420277
DOI: 10.1128/MCB.01780-06 -
Clinical Endocrinology Aug 2018Follow-up data on patients with 46,XY partial gonadal dysgenesis (PGD) until adulthood are scarce, making information on prognosis difficult.
BACKGROUND
Follow-up data on patients with 46,XY partial gonadal dysgenesis (PGD) until adulthood are scarce, making information on prognosis difficult.
OBJECTIVE
To analyse the long-term outcomes of patients with 46,XY PGD regarding testosterone production, germ cell tumour risk, genotype and psychosexual adaptation.
METHODS
A retrospective longitudinal study of 33 patients (20 assigned male and 13 patients assigned female at birth). Molecular diagnosis was performed by Sanger sequencing or by targeted massively parallel sequencing of 63 genes related to disorders of sex development (DSDs).
RESULTS
Age at first and last visit ranged from 0.1 to 43 and from 17 to 53 years, respectively. Spontaneous puberty was observed in 57% of the patients. During follow-up, six of them had a gonadectomy (four due to female gender, and two because of a gonadal tumour). At last evaluation, five of six patients had adult male testosterone levels (median 16.7 nmol/L, range 15.3-21.7 nmol/L) and elevated LH and FSH levels. Germ cell tumours were found in two postpubertal patients (one with an abdominal gonad and one patient with Frasier syndrome). Molecular diagnosis was possible in 11 patients (33%). NR5A1 variants were the most prevalent molecular defects (n = 6), and four of five patients harbouring them developed spontaneous puberty. Gender change was observed in four patients, two from each sex assignment group; all patients reported satisfaction with their gender at final evaluation. Sexual intercourse was reported by 81% of both gender and 82% of them reported satisfaction with their sexual lives.
CONCLUSION
Spontaneous puberty was observed in 57% of the patients with 46,XY PGD, being NR5A1 defects the most prevalent ones among all the patients and in those with spontaneous puberty. Gender change due to gender dysphoria was reported by 12% of the patients. All the patients reported satisfaction with their final gender, and most of them with their sexual life.
PubMed: 29668062
DOI: 10.1111/cen.13717 -
Clinical Kidney Journal Jun 2012Mutations in the WT1 gene, leading to Denys-Drash syndrome and Frasier syndrome, can also cause isolated steroid-resistant nephrotic syndrome (ISRNS). Previous studies...
Mutations in the WT1 gene, leading to Denys-Drash syndrome and Frasier syndrome, can also cause isolated steroid-resistant nephrotic syndrome (ISRNS). Previous studies have reported six pairs of monozygotic twins with WT1 mutations, including one presenting with discordant phenotypes with identical WT1 mutations being of paternal origin and five pairs of monozygotic twins presenting the same phenotype with identical WT1 mutations. In this study, we report on female monozygotic twins showing discordant phenotypes with an identical de novo WT1 mutation, R394W, and presenting incomplete Denys-Drash syndrome and ISRNS.
PubMed: 26069768
DOI: 10.1093/ckj/sfs030 -
Clinical Journal of the American... Apr 2010Wilms tumor-suppressor gene-1 (WT1) plays a key role in kidney development and function. WT1 mutations usually occur in exons 8 and 9 and are associated with...
BACKGROUND AND OBJECTIVES
Wilms tumor-suppressor gene-1 (WT1) plays a key role in kidney development and function. WT1 mutations usually occur in exons 8 and 9 and are associated with Denys-Drash, or in intron 9 and are associated with Frasier syndrome. However, overlapping clinical and molecular features have been reported. Few familial cases have been described, with intrafamilial variability. Sporadic cases of WT1 mutations in isolated diffuse mesangial sclerosis or focal segmental glomerulosclerosis have also been reported.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
Molecular analysis of WT1 exons 8 and 9 was carried out in five members on three generations of a family with late-onset isolated proteinuria. The effect of the detected amino acid substitution on WT1 protein's structure was studied by bioinformatics tools.
RESULTS
Three family members reached end-stage renal disease in full adulthood. None had genital abnormalities or Wilms tumor. Histologic analysis in two subjects revealed focal segmental glomerulosclerosis. The novel sequence variant c.1208G>A in WT1 exon 9 was identified in all of the affected members of the family.
CONCLUSIONS
The lack of Wilms tumor or other related phenotypes suggests the expansion of WT1 gene analysis in patients with focal segmental glomerulosclerosis, regardless of age or presence of typical Denys-Drash or Frasier syndrome clinical features. Structural analysis of the mutated protein revealed that the mutation hampers zinc finger-DNA interactions, impairing target gene transcription. This finding opens up new issues about WT1 function in the maintenance of the complex gene network that regulates normal podocyte function.
Topics: Adolescent; Adult; Age of Onset; Aged; Amino Acid Substitution; Biopsy; Computational Biology; DNA Mutational Analysis; Disease Progression; Exons; Genes, Wilms Tumor; Genetic Predisposition to Disease; Glomerulosclerosis, Focal Segmental; Humans; Italy; Kidney Failure, Chronic; Male; Middle Aged; Models, Molecular; Mutation; Pedigree; Phenotype; Podocytes; Protein Conformation; Proteinuria; Risk Factors; Structure-Activity Relationship; WT1 Proteins
PubMed: 20150449
DOI: 10.2215/CJN.05670809 -
Genes & Development Jul 2002In mammals, several genes including the Wilms tumor suppressor gene Wt1, the Lim homeobox gene Lhx9, and the gene encoding steroidogenic factor 1 (Sf1) have been...
In mammals, several genes including the Wilms tumor suppressor gene Wt1, the Lim homeobox gene Lhx9, and the gene encoding steroidogenic factor 1 (Sf1) have been implicated in the development of the indifferent gonad prior to sexual differentiation. Interactions among these genes have not yet been elucidated. Using biochemical and genetic experiments, we demonstrate here that WT1 and LHX9 function as direct activators of the Sf1 gene. Interestingly, only the -KTS form of WT1 is able to bind to and transactivate the Sf1 promoter. This observation is consistent with differential roles for the -KTS and +KTS variants of WT1 which have been postulated on the basis of human disorders such as the Frasier syndrome. Our data suggest a pathway in which the products of the Wt1 and Lhx9 genes activate expression of Sf1 and thus mediate early gonadogenesis.
Topics: Animals; Base Sequence; Binding Sites; DNA, Complementary; DNA-Binding Proteins; Embryonic and Fetal Development; Female; Fushi Tarazu Transcription Factors; Gene Expression; Genes, Reporter; Genes, Wilms Tumor; Gonads; Homeodomain Proteins; LIM-Homeodomain Proteins; Lac Operon; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Sequence Data; Promoter Regions, Genetic; Protein Isoforms; Receptors, Cytoplasmic and Nuclear; Sex Differentiation; Steroidogenic Factor 1; Trans-Activators; Transcription Factors; Transcriptional Activation; WT1 Proteins
PubMed: 12130543
DOI: 10.1101/gad.220102 -
Post-transplant lymphoproliferative disorder--case reports of three children with kidney transplant.Srpski Arhiv Za Celokupno Lekarstvo 2014Post-transplant lymphoproliferative disorder (PTLD) is a heterogeneous group of diseases, characterized by abnormal lymphoid proliferation following transplantation. It...
INTRODUCTION
Post-transplant lymphoproliferative disorder (PTLD) is a heterogeneous group of diseases, characterized by abnormal lymphoid proliferation following transplantation. It is a disease of the immunosuppressed state, and its occurrence is mostly associated with the use of T-cell depleting agents, and also intensification of immunosuppressive regimens. In the majority of cases, PTLD is a consequence of Epstein-Barr virus (EBV) infection and is a B-cell hyperplasia with CD-20 positive lymphocytes. The 2008 World Health Organization classification for lymphoid malignancies divides PTLD into four major categories: early lesions, polymorphic PTLD, monomorphic PTLD and Hodgkin PTLD. The treatment and prognosis depend on histology. The cornerstone of PTLD therapy includes reduction/withdrawal of immunosuppression, monoclonal anti CD-20 antibody (rituximab) and chemotherapy.
OUTLINE OF CASES
We reported here our experiences with three patients, two girls aged 7.5 and 15 and a 16-year old boy. They had different organ involvement: brain, combined spleen-liver and intestines, respectively. Even though EBV was a trigger of lymphoid proliferation as it was confirmed by histopathology or in cerebrospinal fluid, qualitative EBV-PCR was positive only in one patient at disease presentation. Reduction of immunosuppression therapy was applied in treatment of all three patients, while two of them received rituximab and ganciclovir. They had an excellent outcome besides many difficulties in diagnosis and management of disease.
CONCLUSION
Qualitative EBV-PCR is not useful marker in pediatric transplant recipients. Our suggestion is that patients with the risk factors like T-cell depleting agents, immunosuppressant protocol or increasing immunosuppressive therapy and EBV miss-match with donor must be more accurately monitored with quantitative EBV PCR.
Topics: Adolescent; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents; Child; Epstein-Barr Virus Infections; Female; Frasier Syndrome; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lymphoproliferative Disorders; Male; Nephrotic Syndrome; Polycystic Kidney Diseases; Postoperative Complications; Rituximab
PubMed: 24684038
DOI: 10.2298/sarh1402083s -
Human Genetics Apr 1993The direct involvement of the Wilm's tumor suppressor gene (WT1) in Denys-Drash syndrome through mutations within exons 8 or 9 has recently been established. The absence...
The direct involvement of the Wilm's tumor suppressor gene (WT1) in Denys-Drash syndrome through mutations within exons 8 or 9 has recently been established. The absence of such alterations in three patients with Frasier syndrome provides a molecular basis for distinguishing these two syndromes that are associated with streak gonads, pseudohermaphroditism and renal failure.
Topics: Base Sequence; DNA, Single-Stranded; Female; Genes, Wilms Tumor; Gonadal Dysgenesis; Humans; Kidney Failure, Chronic; Molecular Sequence Data; Polymerase Chain Reaction; Syndrome; Wilms Tumor
PubMed: 8386697
DOI: 10.1007/BF00218274 -
PLoS Genetics Apr 2010Using forward genetics, we have identified the genes mutated in two classes of zebrafish fin mutants. The mutants of the first class are characterized by defects in...
Using forward genetics, we have identified the genes mutated in two classes of zebrafish fin mutants. The mutants of the first class are characterized by defects in embryonic fin morphogenesis, which are due to mutations in a Laminin subunit or an Integrin alpha receptor, respectively. The mutants of the second class display characteristic blistering underneath the basement membrane of the fin epidermis. Three of them are due to mutations in zebrafish orthologues of FRAS1, FREM1, or FREM2, large basement membrane protein encoding genes that are mutated in mouse bleb mutants and in human patients suffering from Fraser Syndrome, a rare congenital condition characterized by syndactyly and cryptophthalmos. Fin blistering in a fourth group of zebrafish mutants is caused by mutations in Hemicentin1 (Hmcn1), another large extracellular matrix protein the function of which in vertebrates was hitherto unknown. Our mutant and dose-dependent interaction data suggest a potential involvement of Hmcn1 in Fraser complex-dependent basement membrane anchorage. Furthermore, we present biochemical and genetic data suggesting a role for the proprotein convertase FurinA in zebrafish fin development and cell surface shedding of Fras1 and Frem2, thereby allowing proper localization of the proteins within the basement membrane of forming fins. Finally, we identify the extracellular matrix protein Fibrillin2 as an indispensable interaction partner of Hmcn1. Thus we have defined a series of zebrafish mutants modelling Fraser Syndrome and have identified several implicated novel genes that might help to further elucidate the mechanisms of basement membrane anchorage and of the disease's aetiology. In addition, the novel genes might prove helpful to unravel the molecular nature of thus far unresolved cases of the human disease.
Topics: Amino Acid Sequence; Animals; Base Sequence; Embryo, Nonmammalian; Extracellular Matrix Proteins; Frasier Syndrome; Furin; Gene Expression Regulation, Developmental; Mice; Molecular Sequence Data; Mutation; Proprotein Convertases; Zebrafish; Zebrafish Proteins
PubMed: 20419147
DOI: 10.1371/journal.pgen.1000907 -
Physiological Genomics Apr 2005Wilms' tumor gene (WT1) is important for nephrogenesis and gonadal growth. WT1 mutations cause Denys-Drash and Frasier syndromes, which are characterized by glomerular... (Comparative Study)
Comparative Study
Wilms' tumor gene (WT1) is important for nephrogenesis and gonadal growth. WT1 mutations cause Denys-Drash and Frasier syndromes, which are characterized by glomerular scarring. To test whether genetic variations in WT1 and WIT1 (gene immediately 5' to WT1) associate with focal segmental glomerulosclerosis (FSGS), patients with biopsy-proven idiopathic and HIV-1-associated FSGS were enrolled in a multicenter study. We genotyped SNP rs6508 located in WIT1 exon 1, three SNPs (rs2301250, rs2301252, rs2301254) in the promoter shared by WT1 and WIT1, rs2234590 in exon 6, rs2234591 in intron 6, rs16754 in exon 7, and rs1799937 in intron 9 of WT1. Cases (n = 218) and controls (n = 281) were compared in the African American population. Stratification by HIV-1 infection status showed that SNPs rs6508, rs2301254, and rs1799937 were significantly associated with FSGS [rs6508 odds ratio (OR) 1.82, P = 0.006; rs2301254 OR 1.65, P = 0.049; rs1799937 OR 1.91, P = 0.005] in the non-HIV-1 group and rs2234591 (OR 0.234, P = 0.011) in the HIV-1 group. Haplotype analyses in the population revealed that seven SNPs were associated with FSGS; five SNPs had the highest contingency score [-log10(P value) = 13.57] in the HIV-1 group. This association could not be explained by population substructure. We conclude that SNPs in WT1 and WIT1 genes are significantly associated with FSGS, suggesting that variants in these genes may mediate pathogenesis by altering WT1 function. Furthermore, HIV-1 infection status interacts with genetic variations in both genes to influence this phenotype. We speculate that nephropathy liability alleles in WT1 pathway genes cause podocyte dysfunction and glomerular scarring.
Topics: Black or African American; Biopsy; Denys-Drash Syndrome; Exons; Female; Frasier Syndrome; Genes, Wilms Tumor; Genetic Variation; Genotype; Glomerulosclerosis, Focal Segmental; Humans; Male; Models, Theoretical; Mutation; Phenotype; Polymorphism, Single Nucleotide; Population
PubMed: 15687485
DOI: 10.1152/physiolgenomics.00201.2004 -
American Journal of Human Genetics Jun 1999
Topics: Female; Genes, Wilms Tumor; Genetic Heterogeneity; Humans; Kidney Diseases; Male; Mutation; Phenotype; Syndrome
PubMed: 10330366
DOI: 10.1086/302409