Denys-Drash Syndrome


Denys-Drash syndrome is a rare condition characterised by renal failure, pseudohermaphroditism, and Wilms Tumor. It is associated with abnormalities of the WT1 gene on chromosome 11.

Literature Analysis

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  • Disease Progression
  • Wilms Tumour
  • WT1
  • Species Specificity
  • Polymerase Chain Reaction
  • Fatal Outcome
  • Frasier Syndrome
  • Renal Insufficiency
  • DNA Mutational Analysis
  • Alternative Splicing
  • Mutation
  • Extracellular Matrix Proteins
  • Kidney Failure, Chronic
  • Heterozygote
  • Infant
  • Newborns
  • Pedigree
  • Adolescents
  • Denys-Drash Syndrome
  • Childhood Cancer
  • Molecular Sequence Data
  • Point Mutation
  • Missense Mutation
  • Disease Models, Animal
  • DNA
  • Young Adult
  • Exons
  • Zinc Fingers
  • Kidney Cancer
  • Wilms Tumor Genes
  • Follow-Up Studies
  • Codon, Nonsense
  • Base Sequence
  • Ovarian Cancer
  • Disorders of Sex Development
  • Karyotyping
  • Kidney Diseases
  • Phenotype
  • Nephrotic Syndrome
Tag cloud generated 29 August, 2019 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (1)

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WT1 11p13 GUD, AWT1, WAGR, WT33, NPHS4, WIT-2, EWS-WT1 -WT1 abnormalities in Denys-Drash Syndrome

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Useful Links (4 links)

Latest Publications

Sun LZ, Wang HY, Li M, et al.
[Clinical and pathological features and mutational types of WT1 mutation-associated nephropathy].
Zhonghua Er Ke Za Zhi. 2018; 56(10):769-774 [PubMed] Related Publications

Wang D, Horton JR, Zheng Y, et al.
Role for first zinc finger of WT1 in DNA sequence specificity: Denys-Drash syndrome-associated WT1 mutant in ZF1 enhances affinity for a subset of WT1 binding sites.
Nucleic Acids Res. 2018; 46(8):3864-3877 [PubMed] Free Access to Full Article Related Publications
Wilms tumor protein (WT1) is a Cys2-His2 zinc-finger transcription factor vital for embryonic development of the genitourinary system. The protein contains a C-terminal DNA binding domain with four tandem zinc-fingers (ZF1-4). An alternative splicing of Wt1 can add three additional amino acids-lysine (K), threonine (T) and serine (S)-between ZF3 and ZF4. In the -KTS isoform, ZF2-4 determine the sequence-specificity of DNA binding, whereas the function of ZF1 remains elusive. Three X-ray structures are described here for wild-type -KTS isoform ZF1-4 in complex with its cognate DNA sequence. We observed four unique ZF1 conformations. First, like ZF2-4, ZF1 can be positioned continuously in the DNA major groove forming a 'near-cognate' complex. Second, while ZF2-4 make base-specific interactions with one DNA molecule, ZF1 can interact with a second DNA molecule (or, presumably, two regions of the same DNA molecule). Third, ZF1 can intercalate at the joint of two tail-to-head DNA molecules. If such intercalation occurs on a continuous DNA molecule, it would kink the DNA at the ZF1 binding site. Fourth, two ZF1 units can dimerize. Furthermore, we examined a Denys-Drash syndrome-associated ZF1 mutation (methionine at position 342 is replaced by arginine). This mutation enhances WT1 affinity for a guanine base. X-ray crystallography of the mutant in complex with its preferred sequence revealed the interactions responsible for this affinity change. These results provide insight into the mechanisms of action of WT1, and clarify the fact that ZF1 plays a role in determining sequence specificity of this critical transcription factor.

Alge JL, Wenderfer SE, Hicks J, et al.
Hemolytic uremic syndrome as the presenting manifestation of WT1 mutation and Denys-Drash syndrome: a case report.
BMC Nephrol. 2017; 18(1):243 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Hemolytic uremic syndrome (HUS) can occur as a primary process due to mutations in complement genes or secondary to another underlying disease. HUS sometimes occurs in the setting of glomerular diseases, and it has been described in association with Denys-Drash syndrome (DDS), which is characterized by the triad of abnormal genitourinary development; a pathognomonic glomerulopathy, diffuse mesangial sclerosis; and the development of Wilms tumor.
CASE PRESENTATION: We report the case of a 46, XX female infant who presented with HUS and biopsy-proven thrombotic microangiopathy. Next generation sequencing of genes with known mutations causative of atypical HUS found that she was homozygous for the Complement Factor H H3 haplotype and heterozygous for a variant of unknown significance in the DGKE gene. Whole exome sequencing identified a de novo heterozygous WT1 c.1384C > T; p.R394W mutation, which is classically associated with Denys-Drash syndrome (DDS). At the time of bilateral nephrectomy five months after her initial biopsy, she had diffuse mesangial sclerosis, typical of Denys-Drash syndrome, without evidence of thrombotic microangiopathy.
CONCLUSION: This unique case highlights HUS as a rare but important manifestation of WT1 mutation and provides new insight into the genetics underlying this association.

Guaragna MS, Ribeiro de Andrade JG, de Freitas Carli B, et al.
WT1 Haploinsufficiency Supports Milder Renal Manifestation in Two Patients with Denys-Drash Syndrome.
Sex Dev. 2017; 11(1):34-39 [PubMed] Related Publications
Denys-Drash syndrome (DDS) is characterized by nephropathy, genital abnormalities, and predisposition to Wilms' tumor. DDS patients usually present heterozygous de novo germline WT1 mutations. The WT1 gene comprises 10 exons encoding the N-terminal transactivation and the C-terminal DNA-binding regions. Two unrelated patients with genital ambiguity and Wilms' tumor were analyzed by sequencing of the WT1 gene, and 3 mutations in exon 1 were identified of which 2 are novel. Patient 1 carried a c.555delC mutation that causes a frameshift and a premature stop codon. Patient 2 carried both c.421A>C and c.424C>T aberrations that lead to the missense p.Lys141Gln and the nonsense p.Lys142* mutation, respectively. As both patients were heterozygous for the mutations, we tested their parents who did not carry any mutation. Therefore, the 3 WT1 mutations occurred de novo in both patients. Heterozygous mutations result in WT1 haploinsufficiency as they impair protein production. They are associated with a milder DDS phenotype as observed in the patients studied here.

Hashimoto H, Zhang X, Zheng Y, et al.
Denys-Drash syndrome associated WT1 glutamine 369 mutants have altered sequence-preferences and altered responses to epigenetic modifications.
Nucleic Acids Res. 2016; 44(21):10165-10176 [PubMed] Free Access to Full Article Related Publications
Mutations in human zinc-finger transcription factor WT1 result in abnormal development of the kidneys and genitalia and an array of pediatric problems including nephropathy, blastoma, gonadal dysgenesis and genital discordance. Several overlapping phenotypes are associated with WT1 mutations, including Wilms tumors, Denys-Drash syndrome (DDS), Frasier syndrome (FS) and WAGR syndrome (Wilms tumor, aniridia, genitourinary malformations, and mental retardation). These conditions vary in severity from individual to individual; they can be fatal in early childhood, or relatively benign into adulthood. DDS mutations cluster predominantly in zinc fingers (ZF) 2 and 3 at the C-terminus of WT1, which together with ZF4 determine the sequence-specificity of DNA binding. We examined three DDS associated mutations in ZF2 of human WT1 where the normal glutamine at position 369 is replaced by arginine (Q369R), lysine (Q369K) or histidine (Q369H). These mutations alter the sequence-specificity of ZF2, we find, changing its affinity for certain bases and certain epigenetic forms of cytosine. X-ray crystallography of the DNA binding domains of normal WT1, Q369R and Q369H in complex with preferred sequences revealed the molecular interactions responsible for these affinity changes. DDS is inherited in an autosomal dominant fashion, implying a gain of function by mutant WT1 proteins. This gain, we speculate, might derive from the ability of the mutant proteins to sequester WT1 into unproductive oligomers, or to erroneously bind to variant target sequences.

Miller-Hodges E
Clinical Aspects of WT1 and the Kidney.
Methods Mol Biol. 2016; 1467:15-21 [PubMed] Related Publications
For more than 30 years, WT1 mutations have been associated with complex developmental syndromes involving the kidney. Acting as a transcription factor, WT1 is expressed throughout the nephron and controls the reciprocal interactions and phenotypic changes required for normal renal development. In the adult, WT1 expression remains extremely high in the renal podocyte, and at a lower level in the parietal epithelial cells. Wt1-null mice are unable to form kidneys [1]. Unsurprisingly, WT1 mutations lead to significant abnormalities of the renal and genitourinary tract, causing a number of human diseases including syndromes such as Denys-Drash syndrome, Frasier syndrome, and WAGR syndrome. Recent methodological advances have improved the identification of WT1 mutations, highlighting its importance even in nonsyndromic renal disease, particularly in steroid-resistant nephrotic syndrome. This vast spectrum of WT1-related disease typifies the varied and complex activity of WT1 in development, disease, and tissue maintenance.

Hillen LM, Kamsteeg EJ, Schoots J, et al.
Refining the Diagnosis of Congenital Nephrotic Syndrome on Long-term Stored Tissue: c.1097G>A (p.(Arg366His)) WT1 Mutation Causing Denys Drash Syndrome.
Fetal Pediatr Pathol. 2016; 35(2):112-9 [PubMed] Related Publications
Congenital nephrotic syndrome (CNS) caused by a mutation in the Wilms tumor 1 suppressor gene (WT1) is part of Denys Drash Syndrome or Frasier syndrome. In the framework of genetic counseling, the diagnosis of CNS can be refined with gene mutation studies on long-term stored formalin-fixed paraffin-embedded tissue from postmortem examination. We report a case of diffuse mesangial sclerosis with perinatal death caused by a de novo mutation in the WT1 gene in a girl with an XY-genotype. This is the first case of Denys Drash Syndrome with the uncommon missense c.1097G>A [p.(Arg366His)] mutation in the WT1 gene which has been diagnosed on long-term stored formalin-fixed paraffin-embedded tissue in 1993. This emphasizes the importance of retained and adequately stored tissue as a resource in the ongoing medical care and counseling.

Carson JM, Okamura K, Wakashin H, et al.
Podocytes degrade endocytosed albumin primarily in lysosomes.
PLoS One. 2014; 9(6):e99771 [PubMed] Free Access to Full Article Related Publications
Albuminuria is a strong, independent predictor of chronic kidney disease progression. We hypothesize that podocyte processing of albumin via the lysosome may be an important determinant of podocyte injury and loss. A human urine derived podocyte-like epithelial cell (HUPEC) line was used for in vitro experiments. Albumin uptake was quantified by Western blot after loading HUPECs with fluorescein-labeled (FITC) albumin. Co-localization of albumin with lysosomes was determined by confocal microscopy. Albumin degradation was measured by quantifying FITC-albumin abundance in HUPEC lysates by Western blot. Degradation experiments were repeated using HUPECs treated with chloroquine, a lysosome inhibitor, or MG-132, a proteasome inhibitor. Lysosome activity was measured by fluorescence recovery after photo bleaching (FRAP). Cytokine production was measured by ELISA. Cell death was determined by trypan blue staining. In vivo, staining with lysosome-associated membrane protein-1 (LAMP-1) was performed on tissue from a Denys-Drash trangenic mouse model of nephrotic syndrome. HUPECs endocytosed albumin, which co-localized with lysosomes. Choloroquine, but not MG-132, inhibited albumin degradation, indicating that degradation occurs in lysosomes. Cathepsin B activity, measured by FRAP, significantly decreased in HUPECs exposed to albumin (12.5% of activity in controls) and chloroquine (12.8%), and declined further with exposure to albumin plus chloroquine (8.2%, p<0.05). Cytokine production and cell death were significantly increased in HUPECs exposed to albumin and chloroquine alone, and these effects were potentiated by exposure to albumin plus chloroquine. Compared to wild-type mice, glomerular staining of LAMP-1 was significantly increased in Denys-Drash mice and appeared to be most prominent in podocytes. These data suggest lysosomes are involved in the processing of endocytosed albumin in podocytes, and lysosomal dysfunction may contribute to podocyte injury and glomerulosclerosis in albuminuric diseases. Modifiers of lysosomal activity may have therapeutic potential in slowing the progression of glomerulosclerosis by enhancing the ability of podocytes to process and degrade albumin.

Hutson JM, Grover SR, O'Connell M, Pennell SD
Malformation syndromes associated with disorders of sex development.
Nat Rev Endocrinol. 2014; 10(8):476-87 [PubMed] Related Publications
When embryological development of the internal and/or external genitalia is disrupted, the patient presents with a disorder of sex development (DSD) in the neonatal period or sometime later in life. Some of these patients have other, nongenital malformations, which makes their overall management more complex than if they just had a DSD. This Review summarises these malformation syndromes and discusses the recent research into their aetiology. The genetic causes of these malformation syndromes, when they are known, will also be described. Many specific genetic mutations are now known in malformation syndromes with a defect in hormonal function. By contrast, the genetic causes remain unknown in many nonhormonal morphological anomalies that affect the genitalia.

Ikezumi Y, Suzuki T, Karasawa T, et al.
Glomerular epithelial cell phenotype in diffuse mesangial sclerosis: a report of 2 cases with markedly increased urinary podocyte excretion.
Hum Pathol. 2014; 45(8):1778-83 [PubMed] Related Publications
We report 2 cases of diffuse mesangial sclerosis (DMS) accompanied by severe podocyte excretion in urine. Patient 1 was a 9-day-old girl with a WT1 mutation who developed Wilms tumor at 6 months of age and was subsequently diagnosed with Denys-Drash syndrome. Patient 2 was a 1-year-old boy without a WT1 abnormality but presenting with heavy proteinuria. In both patients, histological examination showed findings of DMS. Immunohistochemical staining for synaptopodin (a podocyte marker) revealed a reduced number of podocytes in the glomeruli with severe sclerosis; however, podocytes persisted in the relatively intact glomeruli. Some glomeruli were accompanied by sclerotic lesions surrounded by proliferating cells; immunofluorescence staining revealed a majority of these proliferating cells to be positive for claudin-1 (a parietal cell marker) but negative for synaptopodin. These findings suggest that podocyte loss and the consequent proliferation of parietal cells are common processes in the pathogenesis of DMS.

Eneman B, Mekahli D, Audrezet MP, et al.
An unusual presentation of Denys-Drash syndrome due to bigenic disease.
Pediatrics. 2014; 133(1):e252-6 [PubMed] Related Publications
We report a case of Denys-Drash syndrome (DDS) in a 3-month-old girl presenting with bilateral renal cortical cysts mimicking polycystic kidney disease. Genetic analysis revealed a de novo heterozygous missense mutation c.1186G>A (p.Asp396Asn) in the WT1 gene, confirming the diagnosis of DDS. Because multiple renal cysts have never been reported in DDS, we explored several genes responsible for these renal manifestations, such as HNF-1β, PAX2, PKD1, and PKD2. Remarkably, we identified a heterozygous missense variant c.12439A>G (p.Lys4147Glu) in the PKD1 gene. The same variant was found in the patient's mother, who had no renal cysts, and in the grandfather, who had several renal cysts. Mutation prediction programs classified the c.12439A>G variant as being "likely pathogenic." We hypothesize that the severe cystic phenotype in the index patient could be due to the WT1 mutation, enhancing pathogenicity of the "hypomorph" PKD1 allele. A possible role for Wilms tumor suppressor 1 (WT1) in renal cyst development should be considered. From a conceptual point of view, this case shows that an unusual presentation of a known genetic syndrome might point to bigenic inheritance, with unexpected interference of mutated genes causing an uncommon clinical phenotype.

Patel PR, Pappas J, Arva NC, et al.
Early presentation of bilateral gonadoblastomas in a Denys-Drash syndrome patient: a cautionary tale for prophylactic gonadectomy.
J Pediatr Endocrinol Metab. 2013; 26(9-10):971-4 [PubMed] Related Publications
Mutation of the Wilms tumor gene (WT1) is associated with two well-described syndromes called Denys-Drash (DDS) and Frasier (FS). Both are associated with nephropathy and ambiguous genitalia and have overlapping clinical and molecular features. The known risk of Wilms tumor in DDS and gonadoblastoma (GB) in FS patients requires tumor surveillance. The literature reports the occurrence of GB in DDS as lower than FS. This case highlights a very early presentation of bilateral GB in DDS and the consideration of early prophylactic gonadectomy at the time of diagnosis with DDS.

Zhu C, Zhao F, Zhang W, et al.
A familial WT1 mutation associated with incomplete Denys-Drash syndrome.
Eur J Pediatr. 2013; 172(10):1357-62 [PubMed] Related Publications
UNLABELLED: Denys-Drash syndrome (DDS) is a rare disorder characterized by nephropathy, male pseudohermaphroditism, and wilms tumor. Cases are thought to arise sporadically through a de novo mutation in the wilms tumor suppressor gene (WT1), which encodes a zinc finger protein that not only acts as a tumor suppressor but is essential for normal gonadogenesis, nephrogenesis, and development of the urogenital tract. In this report, we describe a family with the well-known missense mutation in exon 9 of the WT1 gene, 1180C>T (R394W), causing incomplete DDS and no symptoms in their father. The proband, a boy with 46, XY karyotype, was born with ambiguous genitalia, penoscrotal hypospadias, and bilateral inguinal hernias. At 2 years of age, he has proteinuria and diffuse mesangial sclerosis, but no wilms tumor has been detected. The elder sister of the proband, at 3 years of age, has normal genitalia, proteinuria, focal mesangial sclerosis but no wilms tumor. The WT1 mutation was detected in both patients, who have suspected DDS, and their father, who is phenotypically normal.
CONCLUSION: This case is unusual in that the 1180C>T mutation, which has been found in approximately 50 % of patients with complete DDS, has been inherited and is causing mild or no symptoms of DDS.

Wang HY, Sun LZ, Yue ZH, et al.
[Clinical and pathological features of Denys-Drash syndrome: report of 3 cases].
Zhonghua Er Ke Za Zhi. 2012; 50(11):855-8 [PubMed] Related Publications
OBJECTIVE: To study the clinical and pathological features of Denys-Drash syndrome (DDS).
METHOD: Three DDS cases who were treated in our department from December 2009 to June 2011 were subjected to this study by reviewing of literature.
RESULT: Both case 1 and case 2 were female, with karyotype 46, XX. Case 3 was male with bilateral cryptorchidism. The ages of nephropathy onset of the three cases were 1 year and 9 months, 2 years and 8 moths, and 3 months respectively. Proteinuria in case 2 and case 3 were evidenced to be resistant to steroid. Case 1 was partially responsive to tacrolimus, plasma albumin and cholesterol were improved, although proteinuria was persistent after Tacrolimus was administered. Remission was achieved in case 2 after administration of cyclosporine A and later tacrolimus, and her renal function remains normal till present (4 years and 9 months). Residue renal histology revealed diffused mesangial sclerosis (DMS) in all three patients. All of the three patients had developed right unilateral Wilms tumor. A novel WT1 missense mutation exon 9 c.1213C > G was detected in case 1. WT1 exon 9 c.1168C > T nonsense mutation and exon 8 c.1130A > T missense mutation were detected in case 2 and case 3, respectively.
CONCLUSION: The clinical manifestation of nephropathy in DDS is variable. The majority present with early onset nephropathy and reach renal failure before the age of 4 years. But in a few patients, nephropathy can also be present much later and progress slowly. Proteinuria in DDS is resistant to steroid but is responsive to calcineurin inhibitors, including Cyclosporine A. The effectiveness of tacrolimus was also observed in this study. DDS is evidently caused by WT1 mutation. DMS is the characteristic renal pathological change in DDS.

Hakan N, Aydin M, Erdogan O, et al.
A novel WT1 gene mutation in a newborn infant diagnosed with Denys-Drash syndrome.
Genet Couns. 2012; 23(2):255-61 [PubMed] Related Publications
Denys-Drash syndrome (DDS) is a rare disorder characterized by glomerulopathy, genital abnormalities and predisposition to Wilms' tumor. It is associated with constitutional Wilms'tumor suppressor 1 (WT1) gene mutations, in which the majority being missense mutations in the zinc-finger region. Here, we present a newborn with DDS, associated with a novel heterozygous missense mutation, p.Asp396His, on exon 9 of WT1.

Yang Y, Feng D, Huang J, et al.
A child with isolated nephrotic syndrome and WT1 mutation presenting as a 46, XY phenotypic male.
Eur J Pediatr. 2013; 172(1):127-9 [PubMed] Related Publications
Mutations in the WT1 gene can lead to Denys-Drash syndrome or Frasier syndrome and can also cause isolated nephrotic syndrome (NS). Most patients with isolated NS caused by WT1 mutations present as 46, XX phenotypic females. There have been two cases with an onset age younger than 3 years with isolated NS caused by WT1 mutations presenting as 46, XY phenotypic males. We present a 46, XY phenotypic male patient with isolated NS and end-stage renal disease (ESRD) at the age of 6.3 years. He had normal male external genitalia with normal penis length and soft and normal volume of both testes. A mutation, 1051A>G (K351E), in exon 8 of WT1 was identified in the patient. After starting hemodialysis, manifestations of hypertension and renal failure improved, but he died at 6.8 years of age as a result of respiratory failure and heart failure. Our study supports the necessity of searching for mutations in WT1 in 46, XY phenotypic male patients with isolated NS and ESRD.

Ogawa Y, Hagiwara M
Challenges to congenital genetic disorders with "RNA-targeting" chemical compounds.
Pharmacol Ther. 2012; 134(3):298-305 [PubMed] Related Publications
Patients of congenital diseases such as Down syndrome (DS) and Duchenne muscular dystrophy (DMD) have abnormalities in their chromosomes and/or genes. Therefore, it has been considered that drug treatments can serve to do little for these patients more than to patch over each symptom temporarily when it arises. Although we cannot normalize their chromosomes and genes with chemical drugs, we may be able to manipulate the amounts and patterns of mRNAs transcribed from patients' DNAs with small chemicals. Based on this simple idea, we have looked for chemical compounds which can be applicable for congenital diseases and found that protein kinase inhibitors such as INDY, TG003, and SRPIN340 are promising as clinical drugs for DS, DMD, and DDS, respectively.

Amin EM, Oltean S, Hua J, et al.
WT1 mutants reveal SRPK1 to be a downstream angiogenesis target by altering VEGF splicing.
Cancer Cell. 2011; 20(6):768-80 [PubMed] Free Access to Full Article Related Publications
Angiogenesis is regulated by the balance of proangiogenic VEGF(165) and antiangiogenic VEGF(165)b splice isoforms. Mutations in WT1, the Wilms' tumor suppressor gene, suppress VEGF(165)b and cause abnormal gonadogenesis, renal failure, and Wilms' tumors. In WT1 mutant cells, reduced VEGF(165)b was due to lack of WT1-mediated transcriptional repression of the splicing-factor kinase SRPK1. WT1 bound to the SRPK1 promoter, and repressed expression through a specific WT1 binding site. In WT1 mutant cells SRPK1-mediated hyperphosphorylation of the oncogenic RNA binding protein SRSF1 regulated splicing of VEGF and rendered WT1 mutant cells proangiogenic. Altered VEGF splicing was reversed by wild-type WT1, knockdown of SRSF1, or SRPK1 and inhibition of SRPK1, which prevented in vitro and in vivo angiogenesis and associated tumor growth.

Yue Z, Pei Y, Sun L, et al.
Clinical pictures and novel mutations of WT1-associated Denys-Drash syndrome in two Chinese children.
Ren Fail. 2011; 33(9):910-4 [PubMed] Related Publications
Denys-Drash syndrome (DDS) is characterized by early onset of nephropathy, genitalia malformation, and Wilms' tumor, where WT1 is the gene that is mutated in most patients. We report two de novo mutations in WT1 found in two Chinese DDS children. Patient 1 was a boy with complete DDS who was presented with progressive nephropathy, unilateral Wilms' tumor, bilateral cryptorchidism, and renal histology showing diffuse mesangial sclerosis (DMS). When the patient was 24 months old, a liver ultrasound showed multiple nodules, and the patient died of pneumonia 1 month later. The de novo novel mutation, c.1130A>T (p.His377Leu), was identified; the mutation replaces histidine with leucine in the zinc finger (Znf) structure and is predicted to change the local spatial structure of the protein. Patient 2 had 46 XX with incomplete DDS and presented with normal genitalia, proteinuria, unilateral Wilms' tumor with renal pedicle lymph node metastasis, and renal histology showing DMS. Her renal function remains normal after 48 months. A de novo mutation, c.1168C>T (p.Arg390Term), was identified; it truncates 60 amino acids at the C terminus, and it is predicted to result in loss of the DNA-binding capacities of the WT1 protein.

da Silva TE, Nishi MY, Costa EM, et al.
A novel WT1 heterozygous nonsense mutation (p.K248X) causing a mild and slightly progressive nephropathy in a 46,XY patient with Denys-Drash syndrome.
Pediatr Nephrol. 2011; 26(8):1311-5 [PubMed] Related Publications
WT1 mutations have been described in a variety of syndromes, including Denys-Drash syndrome (DDS), which is characterized by predisposition to Wilms' tumor, genital abnormalities and development of early nephropathy. The most frequent WT1 defects in DDS are missense mutations located in exons 8-9. Our aim is to report a novel WT1 mutation in a 46,XY patient with a DDS variant, who presented a mild nephropathy with a late onset diagnosed during adolescence. He had ambiguous genitalia at birth. At 4 months of age he underwent nephrectomy (Wilms' tumor) followed by chemotherapy. Ambiguous genitalia were corrected and bilateral gonadectomy was performed. Sequencing of WT1 identified a novel heterozygous mutation (c.742A>T) in exon 4 that generates a premature stop codon (p.K248X). Interestingly, this patient has an unusual DDS nephropathy progression, which reinforces that patients carrying WT1 mutations should have the renal function carefully monitored due to the possibility of late-onset nephropathy.

Furtado LV, Pysher T, Opitz J, et al.
Denys-Drash syndrome with neonatal renal failure in monozygotic twins due to c.1097G>A mutation in the WT1 gene.
Fetal Pediatr Pathol. 2011; 30(4):266-72 [PubMed] Related Publications
Denys-Drash syndrome, characterized by nephrosis, dysgenetic gonads and a predisposition to Wilms tumor, is due to germline mutations in the WT1 gene. We report the pathologic findings on monozygotic twins, both of whom presented with male pseudohermaphroditism, nephrotic syndrome, and progressed to renal failure and death within the first month of life. Sequence analysis of WT1 demonstrated a G-to-A substitution in exon 8 of the gene (c.1097G > A), resulting in an arginine-to-histidine (R366H) substitution in the second zinc finger domain. To the best of our knowledge, this is only the second set of monozygotic twins with Denys-Drash syndrome reported to date.

Lee DG, Han DH, Park KH, Baek M
A novel WT1 gene mutation in a patient with Wilms' tumor and 46, XY gonadal dysgenesis.
Eur J Pediatr. 2011; 170(8):1079-82 [PubMed] Related Publications
Denys-Drash syndrome (DDS) is a rare genetic disorder featuring the triad of Wilms' tumor, early-onset renal failure, and 46, XY disorder of sex development. DDS is usually caused by heterozygous missense mutations in the zinc-finger region of the WT1 gene. The most frequent constitutional WT1 mutations in DDS patients are missense mutations in exons 8 and 9. We present a new case of variable DDS in a child who was found to have a novel heterozygous missense mutation in exon 7 (c.905G>T) and a splicing mutation in exon 6 (IVS6-1G>T).

Stefanidis CJ, Querfeld U
The podocyte as a target: cyclosporin A in the management of the nephrotic syndrome caused by WT1 mutations.
Eur J Pediatr. 2011; 170(11):1377-83 [PubMed] Related Publications
Children with steroid-resistant nephrotic syndrome secondary to WT1-associated glomerulopathies (WT1-GP) were considered unresponsive to cyclosporin A (CsA). This assumption is challenged by the findings of recent studies. The patients of these studies had different types of WT1 mutations and varying clinical presentations. However, all of them were of young age and the favourable response to CsA might be the result of treatment at an early stage of the disease. The additional administration of angiotensin-converting enzyme inhibitors may have contributed to the positive outcome. We review recent data on the role of WT1 in the development of WT1-GP and discuss putative therapeutic targets explaining the therapeutic effect of CsA.

Neuhaus TJ, Arnold W, Gaspert A, et al.
Recurrence of membranoproliferative glomerulonephritis after renal transplantation in Denys-Drash.
Pediatr Nephrol. 2011; 26(2):317-22 [PubMed] Related Publications
Denys-Drash syndrome (DDS) consists of the triad of nephropathy, male pseudohermaphroditism, and Wilms tumor caused by mutations within exons 8 or 9 of the Wilms tumor suppressor gene 1. Early onset nephrotic syndrome progresses to end-stage renal failure. The characteristic histological lesion is diffuse mesangial sclerosis. Here, we report on a boy with DDS who presented early with diffuse mesangial sclerosis, but subsequently also developed immune complex glomerulonephritis with a membranoproliferative pattern (MPGN-pattern GN) in his native kidneys. Four years after renal transplantation, immune complex glomerulonephritis with an MPGN pattern recurred in the renal graft resulting in proteinuria and progressive renal insufficiency.

Wasilewska AM, Kuroczycka-Saniutycz E, Zoch-Zwierz W
Effect of cyclosporin A on proteinuria in the course of glomerulopathy associated with WT1 mutations.
Eur J Pediatr. 2011; 170(3):389-91 [PubMed] Free Access to Full Article Related Publications
Denys-Drash syndrome (DDS) is characterized by progressive glomerulopathy caused by diffuse mesangial sclerosis (DMS), genitourinary defects, and a higher risk of developing Wilms' tumor. It is commonly assumed that the DMS is unresponsive to any medications. In this report, we present a patient with Denys-Drash syndrome, in whom the cyclosporine A (CsA) was found to induce total remission. This observation and observations of other authors confirm that in genetic forms of nephrotic syndrome, the proteinuric effect of CsA may be due to a non-immunologic mechanism. We confirm the beneficial effect of CsA treatment in DDS; however, the potential nephrotoxicity of this drug will probably not allow long-term use.

Guaragna MS, Soardi FC, Assumpção JG, et al.
The novel WT1 gene mutation p.H377N associated to Denys-Drash syndrome.
J Pediatr Hematol Oncol. 2010; 32(6):486-8 [PubMed] Related Publications
SUMMARY: Denys-Drash syndrome (DDS, Online Mendelian Inheritance in Man number 194080) is a rare human developmental disease generally occurring in 46,XY individuals characterized by the combination of disorder of sex development, early onset nephropathy, and Wilms' tumor (WT). DDS is mainly caused by mutations in the WT1 gene. This report describes a novel WT1 gene mutation in a DDS patient. Sequencing the WT1 gene revealed a heterozygous transversion CAT>AAT within exon 8, causing the substitution of an asparagine for a histidine at residue 377. The p.H377N mutation is predicted to diminish the WT1 protein DNA-binding affinity as it might disrupt the normal zinc finger 2 conformation.

Looijenga LH, Hersmus R, de Leeuw BH, et al.
Gonadal tumours and DSD.
Best Pract Res Clin Endocrinol Metab. 2010; 24(2):291-310 [PubMed] Related Publications
Disorders of sex development (DSD), previously referred to as intersex, has been recognised as one of the main risk factors for development of type II germ cell tumours (GCTs), that is, seminomas/dysgerminomas and non-seminomas (e.g., embryonal carcinoma, yolk sac tumour, choriocarcinoma and teratoma). Within the testis, this type of cancer is the most frequent malignancy in adolescent and young adult Caucasian males. Although these males are not known to have dysgenetic gonads, the similarities in the resulting tumours suggest a common aetiological mechanism(s),--genetically, environmentally or a combination of both. Within the group of DSD patients, being in fact congenital conditions, the risk of malignant transformation of germ cells is highly heterogeneous, depending on a number of parameters, some of which have only recently been identified. Understanding of these recent insights will stimulate further research, with the final aim to develop an informative clinical decision tree for DSD patients, which includes optimal (early) diagnosis without overtreatment, such as prophylactic gonadectomy in the case of a low tumour risk.

Ratelade J, Arrondel C, Hamard G, et al.
A murine model of Denys-Drash syndrome reveals novel transcriptional targets of WT1 in podocytes.
Hum Mol Genet. 2010; 19(1):1-15 [PubMed] Related Publications
The Wilms tumor-suppressor gene WT1, a key player in renal development, also has a crucial role in maintenance of the glomerulus in the mature kidney. However, molecular pathways orchestrated by WT1 in podocytes, where it is highly expressed, remain unknown. Their defects are thought to modify the cross-talk between podocytes and other glomerular cells and ultimately lead to glomerular sclerosis, as observed in diffuse mesangial sclerosis (DMS) a nephropathy associated with WT1 mutations. To identify podocyte WT1 targets, we generated a novel DMS mouse line, performed gene expression profiling in isolated glomeruli and identified excellent candidates that may modify podocyte differentiation and growth factor signaling in glomeruli. Scel, encoding sciellin, a protein of the cornified envelope in the skin, and Sulf1, encoding a 6-O endosulfatase, are shown to be expressed in wild-type podocytes and to be strongly down-regulated in mutants. Co-expression of Wt1, Scel and Sulf1 was also found in a mesonephric cell line, and siRNA-mediated knockdown of WT1 decreased Scel and Sulf1 mRNAs and proteins. By ChIP we show that Scel and Sulf1 are direct WT1 targets. Cyp26a1, encoding an enzyme involved in the degradation of retinoic acid, is shown to be up-regulated in mutant podocytes. Cyp26a1 may play a role in the development of glomerular lesions but does not seem to be regulated by WT1. These results provide novel clues in our understanding of normal glomerular function and early events involved in glomerulosclerosis.

Wasilewska A, Zoch-Zwierz W, Tenderenda E, et al.
[WT1 mutation as a cause of progressive nephropathy in Frasier syndrome--case report].
Pol Merkur Lekarski. 2009; 26(156):642-4 [PubMed] Related Publications
Frasier syndrome is an uncommon genetic disorder featuring progressive glomerulopathy, male pseudohermaphroditism and gonadal dysgenesis. It is caused by mutations in intron 9 of the WT1 gene. Because of its rarity there is limited literature available on the diagnosis and treatment of this syndrome. The aim of the study was to present the clinicopathological findings and molecular analysis of phenotypically female adolescent presenting with severe proteinuria and primary amenorrhea. The significance of early recognition of Frasier syndrome and its differentiation from Denys-Drash syndrome was discussed. WT1 mutation analysis should be routinely done in females with steroid-resistant nephritic syndrome.

Ismaili K, Pawtowski A, Boyer O, et al.
Genetic forms of nephrotic syndrome: a single-center experience in Brussels.
Pediatr Nephrol. 2009; 24(2):287-94 [PubMed] Related Publications
The aim of the study was to present our experience in treating children with genetic forms of nephrotic syndrome and diagnosing these diseases. We retrospectively reviewed the clinical data, mutational analyses, histopathological features, treatment modalities, and outcome of 26 consecutive children (20 families) suffering from congenital and/or steroid-resistant nephrotic syndrome who were assessed by genetic analysis. Ten out of 26 children (38%) had congenital nephrotic syndrome, 4/26 (15%) had infantile nephrotic syndrome, 10/26 (38%) had late-onset nephrotic syndrome, and 2/26 (9%) had asymptomatic proteinuria. We detected a mutation in 21/26 (81%) patients and in 15/20 (75%) families. NPHS1 mutation analyses were positive in 4/20 (20%), NPHS2 mutations in 4/20 (20%), WT1 mutations in 4/20 (20%), and PLCE1 mutations in 3/20 (15%) families. NPHS1 and PLCE1 mutations were solely found in patients with the earliest onset. The majority of patients, especially those with early onset of nephrotic syndrome, had serious adverse events related to the nephrotic status, and 19/26 (73%) reached end-stage renal failure at a median age of 27 months. Genetic forms of nephrotic syndrome comprise a heterogeneous group of genetic mutations. The progression toward end-stage renal failure is the rule but is highly variable between patients.

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