Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A complete physical map of the 11p13 region containing the Wilms' tumor locus has been developed and used to localize a candidate Wilms' tumor gene. Our strategy to construct the map combined the use of pulsed-field gel electrophoresis and irradiation-reduced somatic cell hybrids. These hybrids, which contain limited segments of human chromosome 11 segregated from the remainder of the human genome, permit direct visualization of restriction fragments located in 11p13 using human interspersed repeated DNA sequences as hybridization probes. The physical map has provided a framework to identify the sites of genes responsible for the complex of disorders associated with hemizygous 11p13 deletion: Wilms' tumor, aniridia, genitourinary abnormalities, and mental retardation. The Wilms' tumor locus has been limited to a region of less than 345 kb, and a transcript with many of the characteristics expected for the Wilms' tumor gene has been localized to this region.
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PMID:Complete physical map of the WAGR region of 11p13 localizes a candidate Wilms' tumor gene. 215 34

Wilms' tumor is a childhood nephroblastoma that is postulated to arise through the inactivation of a tumor suppressor gene by a two-hit mechanism. A candidate 11p13 Wilms' tumor gene, WT1, has been cloned and shown to encode a zinc finger protein. Patients with the WAGR syndrome (Wilm's tumor, aniridia, genitourinary abnormalities, and mental retardation) have a high risk of developing Wilms' tumor and they carry constitutional deletions of one chromosome 11 allele encompassing the WT1 gene. Analysis of the remaining WT1 allele in a Wilms' tumor from a WAGR patient revealed the deletion of a single nucleotide in exon 7. This mutation likely played a key role in tumor formation, as it prevents translation of the DNA-binding zinc finger domain that is essential for the function of the WT1 polypeptide as a transcriptional regulator.
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PMID:Homozygous inactivation of WT1 in a Wilms' tumor associated with the WAGR syndrome. 768 65

The constitutional chromosomal deletion within the short arm of one copy of chromosome 11, at band p13, which often correlated with WAGR syndrome consisting of Wilms' tumor with aniridia, genitourinary malformation, and mental retardation, provided the first clue to the genetic events in the development of Wilms' tumor. WT1 gene is encoded by 10 exons, resulting in messenger RNA subject to a complex pattern of alternative splicing. WT1 gene encodes a zinc finger transcription factor, which binds to GC-rich sequences and functions as a transcriptional activator or repressor for many growth factor genes. WT 1 protein is mainly expressed in developing kidney, testis, and ovary, indicating that it is involved in the differentiation of genitourinary tissues, all thought to be the sites of origin of Wilms' tumor. The point mutation of WT1 results in Denys-Drash syndrome. The other Wilms' tumor gene, WT2 at 11p15.5, is linked to Beckwith-Wiedemann syndrome. The possibility that WT1 is involved in the etiology of rhabdoid tumor of the kidney was discussed. WT1 is expressed in immortalized hematologic cells such as EBV-LCL and hematologic malignancies, but not in PBL or IL-2L. High level WT1 expression in leukemia cells and a poor prognosis are linked in patients with leukemia, making the gene a novel marker for leukemia cells. A correlated expression between WT1 and mdr-1 in vincristine resistant cells indicates a close relation with multi-drug resistance and is a promising diagnostic marker for chemoresistance in hematologic malignancies.
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PMID:The role of Wilms' tumor genes. 1068 7

The Wilms' tumor gene (WT1) encodes a zinc-finger transcription factor involved in the development of the kidneys and gonads and their subsequent normal function. Mutations in the WT1 gene were identified in patients with WAGR (Wilms' tumor, aniridria, genitourinary abnormalities, and mental retardation), Denys-Drash syndrome, and Frasier syndrome (FS). Constitutional heterozygous mutations of the WT1 gene, almost all located at intron 9, are found in patients with FS. This syndrome is characterized by female external genitalia in 46,XY patients, late renal failure, streak gonads, and high risk of gonadoblastoma development. We report a male with FS with an unusual phenotype characterized by normal penis size with perineal hypospadias, end-stage renal failure at the age of 19 yr, normal adult male serum T levels, extremely elevated gonadotropin levels, para-testicular leiomyoma, unilateral testicular germ cell tumor, bilateral gonadoblastoma, and absence of gonadal dysgenesis. Automatic sequencing identified the IVS9 +4C>T mutation in the WT1 gene, which predicts a change in splice site utilization. WT1 transcript analysis showed reversal of the normal positive/negative KTS (lysine, threonine, and serine) isoform ratio, confirming the diagnosis of FS. This patient with FS presents an external genitalia of Denys-Drash syndrome, suggesting that these two syndromes are not distinct diseases but may represent two ends of a spectrum of disorders caused by alterations in WT1 gene. This case expands the spectrum of phenotypes associated with WT1 mutations, by including predominantly male ambiguous genitalia and absence of gonadal dysgenesis, extremely high gonadotropin levels, and delayed adrenarche, and presence of a para-testicular leiomyoma, bilateral gonadoblastoma, and germ cell neoplasia.
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PMID:An unusual phenotype of Frasier syndrome due to IVS9 +4C>T mutation in the WT1 gene: predominantly male ambiguous genitalia and absence of gonadal dysgenesis. 1205 Feb 5

Anomalies in WT-1 (Wilms' tumor gene), mapped to 11p13, cause Denys-Drash, Frasier and WAGR syndromes. WAGR syndrome is characterized by Wilms' tumor (W), aniridia (A), genitourinary anomalies (G) and mental retardation (R). In the early human fetus, WT-1 is expressed in the pleural and abdominal mesothelium, and consequently this gene may play a role in diaphragm development. The first report of an association between WAGR syndrome and congenital diaphragmatic hernia has recently been published. We present another infant with aniridia, left cryptorchidism with testicular dysgenesis, right-sided posterolateral diaphragmatic hernia and moderate psychomotor retardation, in whom genetic study showed a deletion of 11p13 and PAX-6, confirming the diagnosis of WAGR syndrome.
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PMID:[Association between WAGR syndrome and diaphragmatic hernia]. 1719 30

The WAGR syndrome is a combination of Wilms' tumor, aniridia, genitourinary anomalies, and mental retardation. We report on a 2-year-old boy, who had a deletion of the aniridia gene PAX6 and the Wilms' tumor gene 1 (WT1 gene). At the age of 23 months, a 1.7 x 1.9 cm-sized intrarenal tumor was detected by ultrasound examination. According to the protocol of the SIOP study, a cycle of neoadjuvant chemotherapy was prescribed followed by a left-sided nephrectomy. However, postsurgical histomorphology failed to confirm the suspected diagnosis of Wilms' tumor and instead revealed dysgenetic cysts of the kidney. Based on the image morphology in connection with the deletion of the WT1 gene, the tentative diagnosis of a nephroblastoma had to be made. The study protocol of the SIOP does not permit another therapy algorithm.
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PMID:[Multicystic renal tumor in a patient with WAGR syndrome]. 1729 33