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)

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 describe two unrelated patients with Gillespie syndrome (partial aniridia, cerebellar ataxia, and mental retardation). The typical presentation is the discovery of fixed dilated pupils in a hypotonic infant. The iris abnormality is specific and seems pathognomonic of Gillespie syndrome. It can be distinguished clinically from other forms of aniridia and a presumptive diagnosis of Gillespie syndrome can be made in the first months of life on the basis of the ocular findings. Neurological involvement includes marked motor delay, hypotonia, disabling ataxia, and usually mental retardation. Cerebral and cerebellar atrophy with white matter changes on MRI scan were present in our second patient suggesting that patients with Gillespie syndrome may have more extensive CNS involvement than previously described. The parents of this child were first cousins; thus Gillespie syndrome may be heterogeneous with autosomal recessive and autosomal dominant forms.
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PMID:Gillespie syndrome: a report of two further cases. 921 10

A novel family of genes expressed in human brain has recently been identified. Gene 239FB, transcribed extensively in fetal brain, was isolated from the chromosome 11p13 region associated with mental retardation component of the WAGR (Wilms tumor, aniridia, genitourinary anomalies, mental retardation) syndrome. This report presents a cDNA sequence and expression profile of a related gene, 239AB, isolated from adult brain library, that was mapped to chromosome 22. While similar in structure, the two genes differ in their expression pattern and may have different roles in central nervous system development and function. In contrast to the 239FB, which is expressed predominantly in fetal brain, the 239AB gene is transcribed in adult tissues. Both human genes encode novel proteins of unknown function that are highly conserved from Caenorhabditis elegans to birds and mammals. Phylogenetic analysis suggested that the two lineages of the ancient gene family represented by 239FB and 239AB have been in existence prior to the emergence of modern animals.
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PMID:The 239AB gene on chromosome 22: a novel member of an ancient gene family. 926 72

An incidence of bilateral gonadoblastoma in a 23-month old, mentally retarded boy with congenital sporadic aniridia, undescended dysgenetic testes, deletion of a chromosome (11) (p1302p14.2) and a later occurring unilateral Wilms' tumor is reported. The patient was treated by bilateral gonadectomy, nephrectomy, and chemotherapy, and is alive and well five years later. Another three aniridia/gonablastoma observations from the literature are discussed, two of them without and one in combination with Wilms' tumor. Diagnosis of gonadoblastoma remained unsuspected in two cases until autopsy and in another two cases it was done at surgery. A comparison of four cases reveals common finding--aniridia, dysgenetic gonads, genital abnormalities, mental retardation, deletion of 11p13, early occurrence and bilaterality of gonadoblastoma.
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PMID:Aniridia, gonadoblastoma, Wilms' tumor and deletion 11p13. 958 71

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

A large body of evidence that links alterations of chromosome 11p13 to tumor formation and various developmental disorders has been accumulated. To address the underlying genetic events it would be helpful to have a comprehensive gene map of the region, and this is most readily achieved by generating the complete genomic sequence. Building upon previous mapping and YAC contig analysis we have established a 3-Mb sequence-ready PAC contig. It was constructed by chromosome walking and independently verified by fingerprint analysis of individual clones. The contig starts from the catalase gene on the centromeric side and reaches beyond the PAX6 gene at the 11p13/p14.1 boundary. Additional smaller contigs on either side were identified, but still have to be linked up. The 3-Mb contig spans the central region of deletions encompassing 16 chromosomal breakpoints in patients with WAGR syndrome (Wilms tumor, aniridia, genitourinary malformation, mental retardation), and its construction is an important step in facilitating functional analysis of these genes.
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PMID:A sequence-ready 3-Mb PAC contig covering 16 breakpoints of the Wilms tumor/anirida region of human chromosome 11p13. 979 Jul 64

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 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


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