Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917816 (mental retardation)
 15,867 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Of 40 Wilms tumors with chromosome abnormalities, 6 were hypodiploid, 10 were pseudodiploid, 7 were hyperdiploid with 47 to 49 chromosomes, and 17 were hyperdiploid with 50 or more chromosomes, mostly including +12. WT1 deletions/mutations were found in one hypodiploid, eight pseudodiploid, and one hyperdiploid (47-49 chromosomes) tumor, but in none of the hyperdiploid (> or =50 chromosomes) tumors. Of the 10 tumors with WT1 abnormalities, 6 had a homozygous WT1 deletion, 1 had a nonsense WT1 mutation and loss of heterozygosity at 11p, 1 had an intragenic hemizygous WT1 deletion without detectable WT1 mutation, and 2, which occurred in Wilms tumor-aniridia-genitourinary abnormalities-mental retardation syndrome patients, had a hemizygous deletion and a missense or frameshift mutation of WT1. Six of the nine tumors with homozygous or hemizygous WT1 deletions had chromosome aberrations involving chromosome band 11p13 in one of the two chromosomes 11. While one hypodiploid and one pseudodiploid patient died of the disease, and one hyperdiploid (47-49 chromosomes) patient was alive in nonremission, all hyperdiploid (> or =50 chromosomes) patients had no evidence of disease at the last follow-up. Our data show that chromosome aberrations are closely correlated to WT1 abnormalities and suggest that hyperdiploid (> or =50 chromosomes) Wilms tumors may be characterized by the absence of WT1 abnormalities and possibly also by a favorable prognosis.
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PMID:Correlation of chromosome abnormalities with presence or absence of WT1 deletions/mutations in Wilms tumor. 1022 36

We report a male infant with multiple congenital anomalies and mosaic variegated aneuploidy; a rare cytogenetic abnormality characterized by mosaicism for several different aneuploidies involving many different chromosomes. He had prenatal-onset growth retardation, microcephaly, dysmorphic face, seizures, hypotonia, feeding difficulty, and developmental delay. In addition, he developed bilateral Wilms tumors. Neuroradiological examination revealed Dandy-Walker malformation and hypoplasia of the cerebral hemisphere and pons. Cytogenetic analysis revealed various multiple numerical aneuploidies in blood lymphocytes, fibroblasts, and bone marrow cells, together with premature centromere division (PCD). Peripheral blood chromosome analysis from his parents also showed PCD, but no aneuploid cells. The clinical phenotype and multiple aneuploidies of the patient may be a consequence of the homozygous PCD trait inherited from his parents. Comparison with previously reported cases of multiple aneuploidy suggests that mosaic variegated aneuploidy with PCD may be a clinically recognizable syndrome with major phenotypes being mental retardation, microcephaly, structural brain anomalies (including Dandy-Walker malformation), and possible cancer predisposition.
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PMID:Syndrome of microcephaly, Dandy-Walker malformation, and Wilms tumor caused by mosaic variegated aneuploidy with premature centromere division (PCD): report of a new case and review of the literature. 1042 59

The region p13 of the short arm of human chromosome 11 has been studied intensely during the search for genes involved in the etiology of the Wilms' tumor, aniridia, genitourinary abnormalities, mental retardation (WAGR) syndrome, and related conditions. The gene map for this region is far from being complete, however, strengthening the need for additional gene identification efforts. We describe the extension of an existing contig map with P1-derived artificial chromosomes (PACs) to cover 7.5 Mb of 11p13-14.1. The extended sequence-ready contig was established by end probe walking and fingerprinting and consists of 201 PAC clones. Utilizing bins defined by overlapping PACs, we generated a detailed gene map containing 20 genes as well as 22 anonymous ESTs which have been identified by searching the RH databases. RH maps and our established gene map show global correlation, but the limits of resolution of the current RH panels are evident at this scale. Initial expression studies on the novel genes have been performed by Northern blot analyses. To extend these expression profiles, corresponding mouse cDNA clones were identified by database search and employed for Northern blot analyses and RNA in situ hybridizations to mouse embryo sections. Genomic sequencing of clones along a minimal tiling path through the contig is currently under way and will facilitate these expression studies by in silico gene identification approaches.
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PMID:A 7.5 Mb sequence-ready PAC contig and gene expression map of human chromosome 11p13-p14.1. 1056 47

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

This is a report on the nature of the mutations in the PAX6 gene in twenty patients with aniridia. Five of the twenty patients had sporadic aniridia with deletions in chromosome 11p13. Three of the five had WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, mental retardation), and the other two had deletions whose breakpoints occurred between the PAX6 and the WT1 genes. Allelic losses at PAX6 were of paternal origin. The remaining fifteen patients with aniridia had intragenic mutations in the PAX6 gene, with mutations found from exon 5 to exon 12. Twelve cases of dysfunctional PAX6 were due to premature termination of the protein by nonsense mutations (five cases), splicing defect (one case), deletion (two cases), deletion-insertions (two cases), and tandem repeat insertions (two cases). One patient (P2) had a PAX6 protein with de novo in-frame deletion of alanine, arginine, and proline at codon positions 37, 38, and 39. These codons are in the paired box region, and codon 38 is in contact with the phosphate group of the sugar-phosphate backbone of the target DNA. Another patient (P8) had a single nucleotide transition at c.1182 (nucleotide number, Genbank accession #M93650, used as in Glaser et al. [1992]), which generated both a missense mutation (Q255H) and a splicing defect. A missense mutation was found at G387E in a third patient (P10). All observed mutations support the notion that haploinsufficiency in PAX6 results in aniridia and associated eye anomalies.
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PMID:Mutation in the PAX6 gene in twenty patients with aniridia. 1073 78

We present three patients with variegated aneuploidy and premature centromere division (PCD), a rare chromosomal abnormality in humans. Comparison of these three and eight other patients with variegated aneuploidy related to PCD demonstrates a phenotype comprising most frequently microcephaly, CNS anomalies (with cerebellar affection and migration defects), mental retardation, pre-and postnatal growth retardation, flat and broad nasal bridge, apparently low-set ears, eye and skin abnormalities, and ambiguous genitalia in male patients. The occurrence of Wilms tumor in three patients, rhabdomyosarcoma in two others and acute leukemia in a fifth characterizes this condition as a chromosome or genome instability disorder with a high risk of malignancy. FISH studies in uncultured blood and buccal smear cells demonstrate that the random aneuploidies are not limited to cultured cells, but also occur in vivo.
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PMID:Variegated aneuploidy related to premature centromere division (PCD) is expressed in vivo and is a cancer-prone disease. 1116 58

The convergence of genetic and molecular technologies has led to the identification of a number of genes for male sex determination. The observation of chromosomal translocations, deletions, and duplications in sex reversed individuals was instrumental for the positional cloning of SRY, SOX9, WT1, and DAX1. Cloning by protein-DNA interaction was required for the identification of SF1. The observation of an extended phenotype for the alpha thalassemia-mental retardation syndrome assigned a role for XH2 in the testicular determining process. Over the next several years, new sex determining genes will be identified by linkage analysis in large families with multiple sex reversed members, comparative genomic hybridization of sex reversed individuals, and database searches for genes that encode interacting proteins or paralogs of other species. Given the apparent differences in the sex determining mechanisms of even closely related species, the roles of all of these genes will require confirmation by demonstrating expression in human gonadal ridge at the critical time, and that mutations result in sex reversal.
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PMID:Identifying genes for male sex determination in humans. 1174 5

Fourteen cases of mosaic variegated aneuploidy (MVA) syndrome have been reported in the last 10 years. The phenotype of this rare condition has been quite consistent: severe microcephaly, growth deficiency, mild physical anomalies, and mental retardation. We describe here a young boy in whom MVA syndrome is associated to myelodysplasia with a monosomy 7 bone marrow clone. At the age of 3 years, myelodysplasia progressed to an acute lymphoblastic leukemia, and the patient died soon after. Several syndromes with short stature and severe microcephaly, such as the Seckel and Nijmegen syndromes, comprise hematological findings and chromosome instability. However, chromosome instability was not confirmed in our patient. MVA with hematological findings has not been reported before, but 3 patients of 14 (21%) have developed a malignancy (rhabdomyosarcoma, acute lymphoblastic leukemia, and nephroblastoma). Therefore, we propose that MVA is a condition predisposing to neoplasia.
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PMID:High risk of malignancy in mosaic variegated aneuploidy syndrome. 1256 25

The position of genes within the nucleus has been correlated with their transcriptional activity. The interchromosome domain model of nuclear organization suggests that genes preferentially locate at the surface of chromosome territories. Conversely, high resolution analysis of chromatin fibers suggests that chromosome territories do not present accessibility barriers to transcription machinery. To clarify the relationship between the organization of chromosome territories and gene expression, we have used fluorescence in situ hybridization to analyze the spatial organization of a contiguous approximately 1 Mb stretch of the Wilms' tumor, aniridia, genitourinary anomalies, mental retardation syndrome region of the human genome and the syntenic region in the mouse. These regions contain constitutively expressed genes, genes with tissue-restricted patterns of expression, and substantial regions of intergenic DNA. We find that there is a spatial organization within territories that is conserved between mouse and humans: certain sequences do preferentially locate at the periphery of the chromosome territories in both species. However, we do not detect genes necessarily at the periphery of chromosome territories or at the surface of subchromosomal domains. Intraterritory organization is not different among cell types that express different combinations of the genes under study. Our data demonstrate that transcription of both ubiquitous and tissue-restricted genes is not confined to the periphery of chromosome territories, suggesting that the basal transcription machinery and transcription factors can readily gain access to the chromosome interior.
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PMID:Spatial organization of active and inactive genes and noncoding DNA within chromosome territories. 1199 14

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


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