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Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The chromosome-16 and the X-chromosome forms of alpha-thalassemia--ATR-16 and ATR-X--exemplify 2 important causes of syndromal mental retardation. ATR-16 is a contiguous gene syndrome which arises from loss of DNA from the tip of chromosome 16p13.3 by truncation, interstitial deletion, or unbalanced translocation. It provided the first example of a chromosome translocation that could be detected by molecular analysis but not conventional cytogenetics. It also provided the first example of a telomeric truncation giving rise to a complex genetic syndrome. In contrast ATR-X appears to be due to mutations in a trans-acting factor that regulates gene expression. Mutations in transcription factors have recently been identified in a number of genetic diseases (for example, Denys-Drash syndrome, WT1 [19]; pituitary dwarfism, PIT1 [16]; Rubinstein-Taybi syndrome, CBP [20]. Not only is this mechanism proving to be an important cause of complex syndromes but it is providing new perspectives on certain developmental pathways. XH2 may not be a classical transcription factor but it is certainly involved in the regulation of gene expression, exerting its effects on several different genes. It seems likely that other mutations in this class of regulatory proteins will be found in patients with complex disorders including mental retardation. In broader terms the 2 mechanisms described here may prove to be responsible for a significant proportion of mental retardation. However, without a feature such as alpha-thalassemia to pinpoint the area of genome or pathways involved it may prove difficult to identify other, similarly affected genes underlying other forms of mental retardation. As the human genome project and rapid genome analysis evolve this problem should become less of an obstacle. In the meantime, it is very worthwhile to continue looking for unusual clinical associations that may point to critical genes underlying human genetic disorders.
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PMID:The alpha-thalassemia/mental retardation syndromes. 860 26

Nineteen patients were analysed by fluorescence in situ hybridisation (FISH) with selected 11p13 markers. They were examined because they had either isolated sporadic or familial aniridia, or aniridia with one or more of the WAGR (Wilms' tumour, aniridia, genital anomalies, and mental retardation) syndrome anomalies. The FISH markers from distal 11p13 were cosmids FO2121, PAX6 (aniridia), D11S324, and WT1 (Wilms' tumour predisposition). Two of the patients with isolated aniridia were abnormal, one with an apparently balanced reciprocal 7;11 translocation and an 11p13 breakpoint, which by FISH was shown to be approximately 30 kb distal to the aniridia (PAX6) gene, and the other had a submicroscopic deletion involving part of PAX6 that extended distally for approximately 245 kb. Two patients with aniridia together with other WAGR malformations had deletions involving all four cosmids. One case with aniridia associated with developmental and growth delay had a deletion including FO2121 and PAX6 but not D11S324 and WT1, while in a further case the deletion included all four test cosmids. These studies show that a combined conventional and molecular cytogenetic approach to patients presenting with aniridia is a useful method for differentiating between those with deletions extending into and including WT1 and therefore between those with high and low risks of developing Wilms' tumour.
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PMID:A FISH approach to defining the extent and possible clinical significance of deletions at the WAGR locus. 913 91

We previously established that the expression of the human nov gene (novH) was altered in Wilms' tumors and that levels of novH and WT1 mRNA were inversely correlated in individual Wilms' tumors. Insofar as novH has been shown to be a target for WT1 regulation, novH might play an important role during normal nephrogenesis and in the development of Wilms' tumors. We now show that during normal nephrogenesis novH protein is tightly associated with differentiation of glomerular podocytes. NovH expression is not restricted to renal differentiation but is also detected in endothelium and neural tissue of the kidney. Our results establish that alteration of novH expression in sporadic and heritable Wilms' tumors is associated with dysregulated expression of both novH mRNA and protein. In general, the highest novH expression was noted in the Wilms' tumor, genitourinary anomalies, aniridia, and mental retardation (WAGR)-associated Wilms' tumors. Expression in the Denys-Drash syndrome (DDS)-associated Wilms' tumors fell within the variable spectrum observed in sporadic Wilms' tumor cases. As in developing kidney podocytes, novH protein was also prominent in the abnormal hypoplastic podocytes from DDS cases and in kidney podocytes adjoining Wilms' tumors. In Wilms' tumors exhibiting heterotypic differentiation, novH protein was expressed at high levels in tumor-derived striated muscle and at lower levels in tumor-derived cartilage. These observations taken together indicate that novH may represent both a marker of podocytic differentiation in kidney and a marker of heterotypic mesenchymal differentiation in Wilms' tumors. In addition, absence or very low levels of WT1 are correlated with higher novH expression, and its variable expression in cases with mutant WT1 (sporadic and DDS) suggests that the potential activation and repression transcriptional functions possessed by WT1 are likely dependent on the specific mutation incurred.
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PMID:novH: differential expression in developing kidney and Wilm's tumors. 962 60

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

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

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

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

Aniridia can arise as part of the WAGR syndrome (Wilms tumour. aniridia, genitourinary anomalies, and mental retardation), due to a deletion or chromosomal region 11p13. We report a girl with a complete WAGR syndrome, whose brother presented hypospadias. Cytogenetic, FISH and molecular studies showed a deletion in one chromosome 11 of the patient. No cytogenetic rearrangement or deletion affecting the genes included in this region (PAX6 and WT1) were observed in her brother and parents. This excludes a higher risk than that of the general population for developing Wilms tumour in the brother and supports that the presence of WAGR syndrome in the patient and hypospadias in her brother is a chance association. We conclude that the identification and definition of the deletions in the WAGR region, which include the WT1 locus are important in order to identify a high tumour risk in infant patients with aniridia including those without other WAGR anomalies.
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PMID:Aniridia as part of a WAGR syndrome in a girl whose brother presented hypospadias. 1215 Feb 18

Seventy-seven patients with aniridia, referred for cytogenetic analysis predominantly to assess Wilms tumor risk, were studied by fluorescence in situ hybridization (FISH), through use of a panel of cosmids encompassing the aniridia-associated PAX6 gene, the Wilms tumor predisposition gene WT1, and flanking markers, in distal chromosome 11p13. Thirty patients were found to be chromosomally abnormal. Cytogenetically visible interstitial deletions involving 11p13 were found in 13 patients, 11 of which included WT1. A further 13 patients had cryptic deletions detectable only by FISH, 3 of which included WT1. Six of these, with deletions <500 kb, share a similar proximal breakpoint within a cosmid containing the last 10 exons of PAX6 and part of the neighboring gene, ELP4. Two of these six patients were mosaic for the deletion. The remaining four had chromosomal rearrangements: an unbalanced translocation, t(11;13), with a deletion including the WAGR (Wilms' tumor, aniridia, genitourinary abnormalities, and mental retardation) region, and three balanced rearrangements with what appear to be position effect breakpoints 3' of PAX6: (a) a t(7;11) with the 11p13 breakpoint approximately 30 kb downstream of PAX6, (b) a dir ins(12;11) with a breakpoint >50 kb from PAX6, and (c) an inv(11)(p13q13) with a breakpoint >75 kb downstream of PAX6. The proportion and spectrum of chromosome anomalies in familial (4/14, or 28.5%) and sporadic (26/63, or 41%) cases are not significantly different. An unexpectedly high frequency of chromosomal rearrangements is associated with both sporadic and familial aniridia in this cohort.
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PMID:Frequent chromosome aberrations revealed by molecular cytogenetic studies in patients with aniridia. 1238 36


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