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

Wilms' tumour (WT), aniridia, genitourinary abnormalities and mental retardation form a symptom group (WAGR syndrome) associated with hemizygous deletions of DNA in chromosome band 11p13 (refs 1,2). However, it has not been clear whether hemizygosity at a single locus contributes to more than one phenotype. The tumour suppressor gene for Wilms' tumour, WT1, has been characterized: it is expressed at high levels in the glomeruli of the kidney, as well as the gonadal ridge of the developing gonad, the Sertoli cells of the testis and the epithelial and granulosa cells of the ovary, suggesting a developmental role in the genital system in addition to the kidney. We now report constitutional mutations within the WT1 genes of two individuals with a combination of WT and genital abnormalities as evidence of a role for a recessive oncogene in mammalian development.
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PMID:WT1 mutations contribute to abnormal genital system development and hereditary Wilms' tumour. 165 25

Wilms tumor (WT) is one of the more common childhood cancers. A small fraction of WT occurs in association with aniridia, genitourinary abnormalities and mental retardation, the WAGR syndrome, and these cases often are accompanied by a constitutional deletion of all or part of band 11p13. Recently a WT susceptibility gene (WT1), localized to 11p13, has been isolated and shown to be inactivated in some sporadic WTs. In the present study, a highly informative CA repeat polymorphism within the gene was studied in a family with six affected members in three generations. Predisposition to WT in this large family did not segregate with this polymorphism. Furthermore, linkage analysis indicated exclusion of WT predisposition from 11p15. These results provide definitive evidence that familial predisposition to WT can be mediated by a gene other than WT1.
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PMID:Familial predisposition to Wilms tumor does not segregate with the WT1 gene. 165 33

The distal region of human chromosome band 11p13 is believed to contain a cluster of genes involved in the development of the eye, kidney, urogenital tract, and possibly the nervous system. Genetic abnormalities of this region can lead to Wilms tumor, aniridia, urogenital abnormalities, and mental retardation (WAGR syndrome). Using 11 DNA markers covering the entire distal region of 11p13, including the WAGR region, we have carried out molecular studies on 58 patients with one or more features of this syndrome and patients with other diseases or structural cytogenetic abnormalities associated with 11p13. Cytogenetic analyses were performed in all cases. In 12 patients we were able to demonstrate deletions of this region. In 2 patients balanced translocations and in 2 additional patients duplications of this region were characterized. In total, 5 chromosomal breakpoints within 11p13 were identified. One of these breakpoints maps within the smallest region of overlap of WAGR deletions. Moreover, we were unable to demonstrate constitutional deletions in a candidate sequence for the Wilms tumor gene or any other marker in 2 patients with aniridia and urogenital abnormalities, 4 patients with Wilms tumor and urogenital abnormalities, 5 patients with bilateral Wilms tumors, and 3 familial Wilms tumor cases. We suggest that the molecular techniques used here (heterozygosity testing for polymorphic markers mapping between AN2 and WT1 and deletion analysis by dosage, cytogenetic analysis, or in situ hybridization) can be employed to identify sporadic aniridia patients with and without increased tumor risk.
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PMID:The distal region of 11p13 and associated genetic diseases. 176 47

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 combined use of qualitative and quantitative analysis of 11p13 polymorphic markers together with chromosomal in situ suppression hybridization (CISS) with biotin labeled probes mapping to 11p allowed us to characterize a complex rearrangement segregating in a family. We detected a pericentric intrachromosomal insertion responsible for recurrence of del(11)(p13p14) in the family: an insertion of brand 11p13-p14 carrying the genes for predisposition to Wilms' tumor, WT1, and for aniridia, AN2, into the long arm of chromosome 11 in 11q13-q14. Asymptomatic balanced carriers were observed over three generations. Classical cytogenetics had failed to detect this anomaly in the balanced carriers, who were first considered to be somatic mosaics for del(11)(p13). Two of these women gave birth to children carrying a deleted chromosome 11, most likely resulting from the loss of the 11p13 band inserted in 11q. Although in both cases the deletion encompassed exactly the same maternally inherited markers, there was a wide variation in clinical expression. One child, with the karyotype 46,XY, del(11)(p13p14), presented the full-blown WAGR syndrome with aniridia, mental retardation, Wilms' tumor, and pseudohermaphroditism, but also had proteinuria and glomerular sclerosis reminiscent of Drash syndrome. In contrast, the other one, a girl with the karyotype 46,XX,del(11)(p13), only had aniridia. Although a specific set of mutational sites has been observed in Drash patients, these findings suggest that the loss of one copy of the WT1 gene can result in similar genital and kidney abnormalities.
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PMID:Pericentric intrachromosomal insertion responsible for recurrence of del(11)(p13p14) in a family. 768 57

The Wilms tumour (WT1) gene was first localized through its deletion in individuals with the WAGR syndrome (Wilms tumour, aniridia, genitourinary abnormalities and mental retardation). Such individuals have a 30-50% lifetime risk of developing Wilms tumour and carry constitutional interstitial deletions of chromosome 11p13, including the WT1 gene. Second primary tumours occurring in such individuals might also be related to their genetic predisposition to cancer, as shown for hereditary retinoblastoma. We have found a mutation in the zinc finger region of the remaining WT1 allele in a case of acute myeloid leukaemia developing in a Wilms tumour survivor with the WAGR syndrome. This mutation would be predicted to disrupt DNA binding by this developmentally regulated transcription factor. This finding implicates the WT1 gene in the regulation of myelopoiesis and suggests that WT1 mutations may be found in some sporadic leukaemias.
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PMID:The Wilms tumour (WT1) gene is mutated in a secondary leukaemia in a WAGR patient. 783 22

A human aniridia candidate (AN) gene on chromosome 11p13 has been cloned and characterized. The AN gene is the second cloned gene of the contiguous genes syndrome WAGR (Wilms' tumor, aniridia, genitourinary malformations, mental retardation) on chromosome 11p13, WT1 being the first gene cloned. Knowledge about the position of the AN and WT1 genes on the map of 11p13 makes the risk assessment for Wilms' tumor development in AN patients possible. In this study, we analyzed familial and sporadic aniridia patients for deletions in 11p13 by cytogenetic analyses, in situ hybridization, and pulsed field gel electrophoresis (PFGE). Cytogenetically visible deletions were found in 3/11 sporadic AN cases and in one AN/WT patient, and submicroscopic deletions were identified in two sporadic AN/WT patients and in 1/9 AN families. The exact extent of the deletions was determined with PFGE and, as a result, we could delineate the risk for Wilms' tumor development. Future analyses of specific deletion endpoints in individual AN cases with the 11p13 deletion should result in a more precise risk assessment for these patients.
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PMID:Molecular analysis of aniridia patients for deletions involving the Wilms' tumor gene. 792 24

Six of 39 sporadic Wilms tumors had gross homozygous or hemizygous WT1 and WIT1 deletions. Two Wilms tumor-aniridia-genitourinary abnormalities-mental retardation syndrome patients had total hemizygous WT1 and WIT1 deletions in both constitutional and nonsporadic type tumor cells. Four of the 8 tumors with WT1 and WIT1 deletions showed loss of constitutional heterozygosity (LOH) for markers limited to the 11p13 region. Seven of 19 Wilms tumors with neither WT1 nor WIT1 deletions also had LOH on 11p; 4 in the 11p15-11p13 region, one in the 11p15 and possibly also 11p13 regions, and two solely in the 11p15 region. Thus, 15 of the 41 Wilms tumors (37%) had WT1 and WIT1 deletions or LOH on 11p, and only 2 of the 27 tumors whose nonneoplastic normal tissues were available for study showed LOH limited to the 11p15 region. None of the 7 non-Wilms childhood renal tumors showed WT1 or WIT1 deletions, or LOH on 11p. These data suggest that Japanese Wilms tumors may be characterized by a higher incidence of the gross WT1 deletion and a lower incidence of LOH limited to the 11p15 region than the Caucasian counterparts. These molecular-genetic features may be contributing to the lower incidence of Wilms tumors in Japanese children than in Caucasian ones.
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PMID:Deletion of WT1 and WIT1 genes and loss of heterozygosity on chromosome 11p in Wilms tumors in Japan. 839 32

The genetics and associated abnormalities of Wilms' tumor are reviewed. Wilms' tumor is associated with several congenital syndromes such as WAGR (Wilms' tumor, aniridia, genitourinary malformation, mental retardation) syndrome, Denys-Drash syndrome, Beckwith-Wiedemann syndrome, etc. However, the association with such syndromes is relatively infrequent and accounts for less than 5% of all clinical patients with Wilms' tumor. WAGR syndrome and Denys-Drash syndrome are associated with loss of WT1 gene located in the chromosome 11p13, and BW syndrome is considered to be due to duplication of the paternal 11p15 allele (WT2). The association of Wilms' tumor with primary brain tumors in a daughter and a mother is also described.
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PMID:[Hereditary renal tumors: Wilms' tumor--congenital anomalies' syndrome]. 853 37

The study of Wilms tumor-predisposing congenital syndromes has led to the identification of one tumor-suppressor gene, WT1, and to the localization of WT2. Molecular genetic analyses of these and sporadic Wilms tumors have clarified the role of WT1 in Wilms tumor with aniridia, genitourinary malformations, and mental retardation (WAGR)-syndrome patients, but much remains unclear in the case of WT2 and the Beckwith-Wiedemann syndrome. Loci on chromosomes 16q and 1p have now been implicated in the progression of Wilms tumor and may serve as molecular prognostic markers. It is now clear that Wilms tumors are genetically heterogeneous and may be multigenic in origin. Molecular analyses can now be used for genetic counseling in some children and may become useful in individualizing therapy.
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PMID:Molecular genetics of Wilms tumor. 859 61


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