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Science (New York, N.Y.) Nov 2023Sex determination in mammals depends on the differentiation of the supporting lineage of the gonads into Sertoli or pregranulosa cells that govern testis and ovary...
Sex determination in mammals depends on the differentiation of the supporting lineage of the gonads into Sertoli or pregranulosa cells that govern testis and ovary development, respectively. Although the Y-linked testis-determining gene has been identified, the ovarian-determining factor remains unknown. In this study, we identified -KTS, a major, alternatively spliced isoform of the Wilms tumor suppressor WT1, as a key determinant of female sex determination. Loss of - variants blocked gonadal differentiation in mice, whereas increased expression, as found in Frasier syndrome, induced precocious differentiation of ovaries independently of their genetic sex. In XY embryos, this antagonized expression, resulting in male-to-female sex reversal. Our results identify -KTS as an ovarian-determining factor and demonstrate that its time of activation is critical in gonadal sex differentiation.
Topics: Animals; Female; Male; Mice; Ovary; Sex Determination Processes; Sex-Determining Region Y Protein; Testis; WT1 Proteins; Protein Isoforms
PubMed: 37917714
DOI: 10.1126/science.add8831 -
Children (Basel, Switzerland) Jul 2021Frasier syndrome is a rare disease that affects the kidneys and genitalia. Patients who have Frasier syndrome develop nephrotic syndrome (NS) featuring focal segmental...
Frasier syndrome is a rare disease that affects the kidneys and genitalia. Patients who have Frasier syndrome develop nephrotic syndrome (NS) featuring focal segmental glomerulosclerosis (FSGS) that is resistant to steroid treatment in early childhood. Male patients can have female external genitalia (pseudo-hermaphroditism) at birth and develop gonado-blastoma in their adolescence. Frasier syndrome is caused by mutations in the splice donor site at intron 9 of the Wilms' tumor gene; these mutations result in an imbalanced ratio of WT1 protein isoforms and affect the development of the urogenital tract, podocyte function, and tumor suppression. Here, we report on a patient with long-term refractory NS who developed a malignant mixed germ cell tumor arising in a gonado-blastoma of the ovary 8 years after the onset of proteinuria.
PubMed: 34438508
DOI: 10.3390/children8080617 -
Cureus Aug 2023While the acute phase of the COVID-19 pandemic has largely come to pass, the chronic physiologic effects of the coronavirus continue to unfold. Specifically, the number... (Review)
Review
While the acute phase of the COVID-19 pandemic has largely come to pass, the chronic physiologic effects of the coronavirus continue to unfold. Specifically, the number of COVID-19-associated vasculitis cases has steadily increased since the onset of the pandemic. Data have shown that vasculitis may develop less than two weeks after COVID-19 or during a later onset of the disease. At this time, research has demonstrated that the novel coronavirus invades more than just the lungs; it can also attack the nervous system, cardiovascular system, and kidneys. In addition, there is a greater understanding of the pathogenesis regarding COVID-19-induced vasculitis via humoral immunity and immune complex disease. Recent case reports have shown an association between COVID-19 and secondary vasculitis. This review paper discusses case reports and data that suggest that COVID-19 may lead to specific vasculitis diseases such as giant cell arteritis, ophthalmic arteritis, aortitis, and Kawasaki-like disease. More research needs to be performed on this association to aid in diagnosis and treatment.
PubMed: 37638271
DOI: 10.7759/cureus.44119 -
Pediatric Nephrology (Berlin, Germany) Oct 2022Intronic WT1 mutations are usually causative of Frasier syndrome with focal segmental glomerulosclerosis as the characteristic nephropathy. Membranoproliferative... (Review)
Review
BACKGROUND
Intronic WT1 mutations are usually causative of Frasier syndrome with focal segmental glomerulosclerosis as the characteristic nephropathy. Membranoproliferative glomerulonephritis is not commonly associated with disorders of sex development but has been recently identified as a WT1-associated nephropathy, but usually in cases of exonic mutations in either isolated Wilms tumor or Denys-Drash syndrome.
METHODS
The clinical and genetic data from 3 individuals are reported.
RESULTS
This report describes the kidney manifestations in 3 individuals from 2 unrelated families with Frasier syndrome intronic WT1 mutations, noting that 2 of the 3 individuals have histologically confirmed membranoproliferative glomerulonephritis.
CONCLUSIONS
These case reports support expansion of the clinical spectrum of the kidney phenotypes associated with Frasier syndrome providing evidence of an association between WT1 mutation and an immune complex-related membranoproliferative glomerulonephritis. A higher resolution version of the Graphical abstract is available as Supplementary information.
Topics: Denys-Drash Syndrome; Frasier Syndrome; Genes, Wilms Tumor; Glomerulonephritis, Membranoproliferative; Gonadal Dysgenesis; Humans; Kidney Neoplasms; Mutation; WT1 Proteins; Wilms Tumor
PubMed: 35211794
DOI: 10.1007/s00467-022-05421-8 -
BMC Nephrology Aug 2020Mutations in the Wilms tumor 1 gene cause a spectrum of podocytopathy ranging from diffuse mesangial sclerosis to focal segmental glomerulosclerosis. In a considerable... (Review)
Review
BACKGROUND
Mutations in the Wilms tumor 1 gene cause a spectrum of podocytopathy ranging from diffuse mesangial sclerosis to focal segmental glomerulosclerosis. In a considerable fraction of patients with Wilms tumor 1 mutations, the distinctive histology of immune-complex-type glomerulonephritis has been reported. However, the clinical relevance and etiologic mechanisms remain unknown.
CASE PRESENTATION
A 5-year-old child presented with steroid-resistant nephrotic range proteinuria. Initial renal biopsy revealed predominant diffuse mesangial proliferation with a double-contour and coexisting milder changes of focal segmental glomerulosclerosis. Immunofluorescence and electron microscopy revealed a full-house-pattern deposition of immune complexes in the subendothelial and paramesangial areas. Serial biopsies at 6 and 8 years of age revealed that more remarkable changes of focal segmental glomerulosclerosis had developed on top of the initial proliferative glomerulonephritis. Identification of a de novo Wilms tumor 1 splice donor-site mutation in intron 9 (NM_024426.6:c.1447 + 4C > T) and 46,XY-gonadal dysgenesis led to the diagnosis of Frasier syndrome.
CONCLUSIONS
Our findings, together with those of others, point to the importance of heterogeneity in clinicopathological phenotypes caused by Wilms tumor 1 mutations and suggest that immune-complex-mediated membranoproliferative glomerulopathy should be considered as a histological variant.
Topics: Antigen-Antibody Complex; Child; Child, Preschool; Disease Progression; Frasier Syndrome; Glomerulonephritis, Membranoproliferative; Glomerulosclerosis, Focal Segmental; Humans; Kidney; Male; WT1 Proteins
PubMed: 32838737
DOI: 10.1186/s12882-020-02007-0 -
Kidney International Reports Oct 2021Frasier syndrome (FS) is a rare inherited kidney disease caused by intron 9 splicing variants of . For wild-type , 2 active splice donor sites in intron 9 cause a...
INTRODUCTION
Frasier syndrome (FS) is a rare inherited kidney disease caused by intron 9 splicing variants of . For wild-type , 2 active splice donor sites in intron 9 cause a mixture of 2 essential transcripts (with or without lysine-threonine-serine [+/KTS or -KTS]), and imbalance of the +KTS/-KTS ratio results in the development of FS. To date, 6 causative intron 9 variants have been identified; however, detailed transcript analysis has not yet been conducted and the genotype-phenotype correlation also remains to be elucidated.
METHODS
We conducted an minigene splicing assay for 6 reported causative variants and RNA sequencing to determine the +KTS/-KTS ratio using patients' samples. We also performed a systematic review of reported FS cases with a description of the renal phenotype.
RESULTS
The assay revealed that although all mutant alleles produced -KTS transcripts only, the wild-type allele produced both +KTS and -KTS transcripts at a 1:1 ratio. RNA sequencing showed that patients' samples with all heterozygous variants produced similar ratios of +KTS to -KTS (1:3.2-1:3.5) and wild-type kidney showed almost a 1:1 ratio (1:0.85). A systematic review of 126 cases clarified that the median age of developing ESKD was 16 years in all FS patients, and there were no statistically significant differences between the genotypes or sex chromosome karyotypes in terms of the renal survival period.
CONCLUSION
Our study suggested no differences in splicing pattern or renal survival period among reported intron 9 variants causative of FS.
PubMed: 34622098
DOI: 10.1016/j.ekir.2021.07.010 -
Children (Basel, Switzerland) Mar 2023Frasier syndrome (FS) is a rare inherited disorder characterized by gonadal dysgenesis and progressive nephropathy, resulting from mutations in the intron 9 splice donor...
Frasier syndrome (FS) is a rare inherited disorder characterized by gonadal dysgenesis and progressive nephropathy, resulting from mutations in the intron 9 splice donor site of the Wilms tumor 1 (WT1) gene. It is associated with male gonadal dysgenesis (female external genitalia with a 46 XY karyotype), and a high risk of gonadoblastoma during adolescence. Patients with FS present early in childhood with proteinuria that progressively worsens with a high likelihood of end-stage renal disease (ESRD). Herein, we report a 15-year-old female (karyotype 46, XY) patient characterized by delayed puberty and steroid-resistant nephrotic syndrome, in whom whole genome sequencing showed a mutation in intron 9 of the WT1 gene, c.1447 + 4 C>T. This is the first case of FS with delayed puberty as the first complaint with no previous renal symptoms. We consider delayed puberty as an important manifestation of FS and summarize the diagnostic process of delayed puberty in the female phenotype. For clinicians, delayed puberty is a common disorder in pediatrics but requires vigilance for some rare causes. Etiological screening and chromosome karyotype analysis are important for the early diagnosis of FS in patients with delayed puberty.
PubMed: 36980135
DOI: 10.3390/children10030577 -
Srpski Arhiv Za Celokupno Lekarstvo 2013Frasier syndrome (FS) is a genetic form of glomerulopathy, which results from mutations in the Wilms'tumour suppressor gene (WT1). Proteinuria in FS has been...
INTRODUCTION
Frasier syndrome (FS) is a genetic form of glomerulopathy, which results from mutations in the Wilms'tumour suppressor gene (WT1). Proteinuria in FS has been traditionally considered unresponsive to any medication and FS inevitably progresses to end stage renal failure.
CASE OUTLINE
We present a patient with FS who had atypical clinical manifestation and unusual beneficial antiproteinuric response to renin-angiotensin system (RAS) inhibitors given in combination with indomethacin. After 13 years of follow-up, the patient is now 17-year old with normal renal functions and no proteinuria.
CONCLUSION
RAS inhibitors combined with indomethacin showed beneficial effect in our patient. Thus, this combination might be the initial treatment of patients with FS. If this treatment strategy was not satisfied for at least 3 months, then CsA would be considered to be administered taking account of the nephrotoxicity and the increased risk of malignancy. Further prospective study is required to clarify this issue.
Topics: Angiotensin-Converting Enzyme Inhibitors; Anti-Inflammatory Agents, Non-Steroidal; Child, Preschool; Female; Frasier Syndrome; Humans; Proteinuria
PubMed: 24364235
DOI: 10.2298/sarh1310685p -
International Medical Case Reports... 2021Frasier syndrome is a rare genetic nephropathy characterized by the presence of progressive glomerulopathy with proteinuria associated with male pseudo hermaphroditism....
OBJECTIVE
Frasier syndrome is a rare genetic nephropathy characterized by the presence of progressive glomerulopathy with proteinuria associated with male pseudo hermaphroditism. This case study described a picture of a young boy where the clinical suspicion context reminded the Frasier syndrome. To our knowledge, this case is the first described in Haiti.
CASE STUDY
This is a 19-year-old young phenotypically male, born with a genital anomaly, was seen on referral at the nephrology/dialysis unit of the internal medicine department of the State University Hospital of Haiti for evaluation and follow-up. Insidious progression of symptoms had occurred over 3 years. Over three months of outpatient follow-up, he had four sets of renal labs drawn, and all showed impaired renal function. At the ultrasound, a bilateral cryptorchidism is described in the inguinal, and presence of functional ovaries with follicles of variable size scattered in the parenchyma. So, in the light of these anamnestic, clinical and paraclinical findings, we concluded to the diagnosis of end-stage renal failure by progressive glomerulopathy in a context of Frasier's syndrome.
CONCLUSION
With any clinical picture consisting of genital anomalies at birth, renal symptomatology during childhood and the diagnosis of renal failure during adolescence, rare genetic nephropathies, such as Frasier syndrome must be considered.
PubMed: 34408503
DOI: 10.2147/IMCRJ.S325619