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Journal of Indian Association of... 2015
PubMed: 26628814
DOI: 10.4103/0971-9261.154641 -
Kidney International Dec 2016The WT1 (Wilm's tumor suppressor) gene is expressed throughout life in podocytes and is essential for the functional integrity of the glomerular filtration barrier....
The WT1 (Wilm's tumor suppressor) gene is expressed throughout life in podocytes and is essential for the functional integrity of the glomerular filtration barrier. We have previously shown that CMIP (C-Maf inducing protein) is overproduced in podocyte diseases and alters intracellular signaling. Here we isolated the proximal region of the human CMIP promoter and showed by chromatin immunoprecipitation assays and electrophoretic-mobility shift that Wilm's tumor protein (WT1) bound to 2 WT1 response elements, located at positions -290/-274 and -57/-41 relative to transcription start site. Unlike the human CMIP gene, only one Wt1 response element was identified in the mouse Cmip proximal promoter located at position -217/-206. Luciferase reporter assays indicated that WT1 dose-dependently inhibited the transcriptional induction of the CMIP promoter. Transfection of decoy oligonucleotides mimicking the WT1 response elements prevented the inhibition of WT1 on CMIP promoter activity. Furthermore, WT1 silencing promoted Cmip expression. In line with these findings, the abundance of Cmip was early and significantly increased at the transcript and protein level in podocytes displaying a primary defect in Wt1, including Denys-Drash syndrome and Frasier syndrome. Thus, WT1 is a major repressor of the CMIP gene in physiological situations, while conditional deletion of CMIP in the developing kidney did not affect the development of mature glomeruli.
Topics: Adaptor Proteins, Signal Transducing; Animals; Base Sequence; Denys-Drash Syndrome; Female; Frasier Syndrome; Gene Expression Regulation; Humans; Kidney; Male; Mice; Podocytes; Promoter Regions, Genetic; WT1 Proteins
PubMed: 27650733
DOI: 10.1016/j.kint.2016.07.016 -
Genetics and Molecular Research : GMR Mar 2016Mutations in the Wilms' tumor gene, WT1, can lead to syndromic steroid-resistant nephrotic syndrome and isolated steroid-resistant nephrotic syndrome. WT1 mutations have...
Mutations in the Wilms' tumor gene, WT1, can lead to syndromic steroid-resistant nephrotic syndrome and isolated steroid-resistant nephrotic syndrome. WT1 mutations have been identified in the majority of children with Denys-Drash or Frasier syndrome. WT1 mutations have not previously been identified in boys with sporadic isolated steroid-resistant nephrotic syndrome, but, recently, four boys with isolated nephrotic syndrome were identified to have WT1 mutations. However, whether boys with sporadic isolated steroid-resistant nephrotic syndrome should be routinely subjected to mutation analysis of WT1 has not been established. We examined 35 boys with sporadic isolated steroid-resistant nephrotic syndrome for mutations in WT1. Mutation analysis of all 10 exons of WT1 was performed by polymerase chain reaction and direct sequencing. Karyotype analysis or Y chromosome identification was performed for all patients. A Y chromosome or a 46, XY karyotype was demonstrated for all 35 patients. No causative WT1 mutation was identified in any of the patients. The WT1 mutation, IVS4+14T>C, which is not predicted to affect splicing, was identified in one patient who achieved complete remission after 8 weeks of oral prednisone treatment, indicating that IVS4+14T>C is not a causative mutation. Five WT1 polymorphisms were also identified in some patients and controls. Our results suggest that mutation analysis of WT1 should not be routinely performed for genetically defined boys with sporadic isolated steroid-resistant nephrotic syndrome.
Topics: Adolescent; Child; Child, Preschool; DNA Mutational Analysis; Drug Resistance; Exons; Humans; Infant; Male; Mutation; Nephrotic Syndrome; Polymorphism, Genetic; Prednisone; WT1 Proteins
PubMed: 26985958
DOI: 10.4238/gmr.15017559 -
The Journal of Urology Mar 2017We sought to determine the presence of germ cells in the gonads of patients with disorders of sex development to establish whether preservation of germ cells for future...
PURPOSE
We sought to determine the presence of germ cells in the gonads of patients with disorders of sex development to establish whether preservation of germ cells for future fertility potential is possible. We hypothesized that germ cells are present but vary by age and diagnosis.
MATERIALS AND METHODS
We reviewed histology from patients with disorders of sex development who underwent gonadectomy/biopsy from 2002 to 2014 at a single institution for pathological classification of the gonad, composition of gonadal stroma and germ cell presence.
RESULTS
A total of 44 patients were identified and germ cells were present in 68%. The presence and average number of germ cells per mm were analyzed by gonad type and diagnosis. By gonad type all ovotestes, most testes, ovaries and dysgenetic testes, and 15% of streak gonads had germ cells present. By diagnosis germ cells were present in all patients with complete androgen insensitivity syndrome, Denys-Drash syndrome, SRY mutation, mixed gonadal dysgenesis, ovotesticular conditions and StAR (steroid acute regulatory protein) deficiency, in some patients with persistent müllerian duct syndrome, XO/XY Turner syndrome and disorders of sex development not otherwise specified, and in none with complete or partial gonadal dysgenesis. Germ cells were present in the gonads of 88% of patients 0 to 3 years old, 50% of those 4 to 11 years old and 43% of those older than 12 years.
CONCLUSIONS
Germ cells were present in the majority of our cohort and the presence decreased with age. This novel, fertility driven evaluation of germ cell quantity in a variety of disorders of sex development suggests that fertility potential may be greater than previously thought. Further studies must be done to evaluate a larger population and examine germ cell quality to determine the viability of these germ cells.
Topics: Adolescent; Child; Child, Preschool; Disorders of Sex Development; Female; Fertility Preservation; Germ Cells; Humans; Infant; Infant, Newborn; Infertility; Male; Ovary; Testis
PubMed: 27840018
DOI: 10.1016/j.juro.2016.08.108 -
Transplantation Direct Dec 2016We report here the first successful transplant from a preterm cadaveric donor. This was performed in November 1994. The donor, who had been born at about 33 weeks of...
BACKGROUND
We report here the first successful transplant from a preterm cadaveric donor. This was performed in November 1994. The donor, who had been born at about 33 weeks of gestation, was diagnosed as having agenesis of the corpus callosum. The transplant was carried out 10 days after the donor's birth. The recipient was a 17-month-old boy with a diagnosis of Denys-Drash syndrome (WT1 mutation).
METHOD
We describe and analyze the ethical, social, cultural, medical and surgical issues encountered and how these were addressed. The major issue of determining death in a beating heart, very young donor was dealt with in the absence of worldwide experience and guidelines.
RESULTS
The transplanted recipient has lived with the grafted pair of kidneys for more then 22 years. He has led a relatively normal life.
CONCLUSIONS
It is possible for immature preterm deceased donor kidneys to be transplanted into a 17-month-old recipient and for the grafted kidneys to grow with the recipient and function for 22 years. There were challenges in ethically determining the death of the donor, in surgical techniques to obviate potential surgical complications, and in postoperative care of the recipient, but these were managed successfully.
PubMed: 27990482
DOI: 10.1097/TXD.0000000000000631 -
Kidney International Mar 2019
Topics: Adult; Biopsy; Denys-Drash Syndrome; Graft Rejection; Humans; Immunocompromised Host; Immunosuppression Therapy; Kidney Transplantation; Male; Mycobacterium Infections, Nontuberculous; Mycobacterium marinum; Skin; Upper Extremity
PubMed: 30784666
DOI: 10.1016/j.kint.2018.10.012