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

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 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

Genetic studies in families with X linked mental retardation have suggested the location of several MR genes in the human q21 region. Since the establishment of cloned resources is an essential step towards the cloning of genes involved in inherited diseases, we built a yeast artificial chromosome (YAC) contig and an STS map of this part of the X chromosome. The contig, which extends from PGK1 in Xq13.3 to DXS1002 in Xq21.2, consists of 30 YACs mapped with 21 markers and spans about 6 Mb. The YAC contig was used as a framework to localise several previously known genes and CEPH/Genethon polymorphic markers, as well as to construct a physical map of the region surrounding one of these genes. We recently localised a presumed MR locus to the region flanked by DXS233 (proximal) and CHM (distal). In the present work, the zinc finger gene, ZNF6, has been shown to lie within this region and to be highly expressed in brain, making it a good candidate MR gene. Similarly the VDAC1 gene has been mapped between DXS986 and DXS72 and its candidate gene status for the Allan-Herndon-Dudley syndrome is discussed.
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PMID:Localisation of two candidate genes for mental retardation using a YAC physical map of the Xq21.1-21.2 subbands. 873 41

The XNP/ATR-X gene is involved in several X-linked mental retardation phenotypes: the ATR-X syndrome, the Juberg-Marsidi syndrome, and some severe mental retardation phenotypes without alpha-thalassemia. Using a vectorette strategy, we have identified and sequenced the intron/exon boundaries of this gene. The gene is composed of 35 exons. It encodes a potential protein of 2492 amino acids. A search of the databases identified three zinc finger motifs within the 5' end of the gene. Expression analysis in different tissues indicated that an alternative splicing event that involves exon 6 is occurring. One of these alternatively spliced transcripts is predominantly expressed in embryonic tissues. These data led us to search for mutations in the 5' region in ATRX patients without other mutations in the 3' region. In one patient a mutation was found in which part of exon 7 was removed from the XNP transcript, as a result of a mutation creating a novel splice site that is substituted for the natural splice site. This new splicing event removed one zinc finger motif. This is the first example of a mutation in XNP within the 5' coding region. It suggests that mutations will be predominantly found in the helicase region as well as in the zinc finger regions and leads us to propose a large screening of additional patients.
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PMID:Determination of the genomic structure of the XNP/ATRX gene encoding a potential zinc finger helicase. 924 31

Chromosome 8p11-12 is the site of a recurrent breakpoint in a myeloproliferative disorder that involves lymphoid (T- or B-cell), myeloid hyperplasia and eosinophilia, and evolves toward acute leukemia. This multilineage involvement suggests the malignant transformation of a primitive hematopoietic stem cell. In this disorder, the 8p11-12 region is associated with three different partners 6q27, 9q33, and 13q12. We describe here the molecular characterization of the t(8;13) translocation that involves the FGFR1 gene from 8p12, encoding a tyrosine kinase receptor for members of the fibroblast growth factor family, and a gene from 13q12, tentatively named FIM (Fused In Myeloproliferative disorders). FIM is related to DXS6673E, a candidate gene for X-linked mental retardation in Xq13.1; this defines a gene family involved in different human pathologies. The two reciprocal fusion transcripts, FIM/FGFR1 and FGFR1/FIM are expressed in the malignant cells. The FIM/FGFR1 fusion protein contains the FIM putative zinc finger motifs and the catalytic domain of FGFR1. We show that it has a constitutive tyrosine kinase activity.
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PMID:Fibroblast growth factor receptor 1 is fused to FIM in stem-cell myeloproliferative disorder with t(8;13). 957 49

X-linked alpha-thalassemia/mental retardation syndrome (ATR-X) is one of the many known X-linked mental retardation syndromes. Mutations in the ATR-X gene (ATRX) that encodes a putative global transcription factor have been identified in patients with ATR-X as well as those with other forms of X-linked mental retardation syndrome. To better understand the genetic basis of ATR-X, we investigated nine patients with the ATR-X phenotype from eight independent Japanese families for mutations in ATRX. We identified seven missense mutations, including six novel mutations, all of which were located either in the N-terminal region corresponding to the putative zinc finger domain (N179S, P190L, V194I, and R246C) or in the C-terminal region corresponding to the helicase domain (V1552F, L1645S, and Y1847C). R246C was found in two independent patients. Furthermore, we investigated the origin of the mutations in seven mothers. Five mothers were found to be carriers, and two were not, indicating de novo origin of the mutations. When we compared clinical manifestations with respective mutations, we could not find apparent phenotype-genotype correlation. Therefore, the putative zinc finger domain and the helicase domains may have similar functional significance for the function of ATRX.
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PMID:Molecular genetic study of japanese patients with X-linked alpha-thalassemia/mental retardation syndrome (ATR-X). 1099 12

Mutations in the XNP/ATR-X gene, located in Xq13.3, are associated with several X linked mental retardation syndromes, the best known being alpha thalassaemia with mental retardation (ATR-X). The XNP/ATR-X protein belongs to the family of SWI/SNF DNA helicases and contains three C2-C2 type zinc fingers of unknown function. Previous studies have shown that 65% of mutations of XNP have been found within the zinc finger domain (encoded by exons 7, 8, and the beginning of exon 9) while 35% of the mutations have been found in the helicase domain extending over 3 kb at the C-terminus of the protein. Although different types of mutations have been identified, no specific genotype-phenotype correlation has been found, suggesting that gene alteration leads to a loss of function irrespective of mutation type. Our aims were to understand the function of the XNP/ATR-X protein better, with specific attention to the functional consequences of mutations to the zinc finger domain. We used monoclonal antibodies directed against the XNP/ATR-X protein and performed immunocytochemical and western blot analyses, which showed altered or absent XNP/ATR-X expression in cells of affected patients. In addition, we used in vitro experiments to show that the zinc finger domain can mediate double stranded DNA binding and found that the DNA binding capacity of mutant forms in ATR-X patients is severely reduced. These data provide insights into the understanding of the functional significance of XNP/ATR-X mutations.
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PMID:ATR-X mutations cause impaired nuclear location and altered DNA binding properties of the XNP/ATR-X protein. 1101 51

Hirschsprung disease (HD) has been described in association with microcephaly, mental retardation and characteristic facial features, delineating a syndrome possibly caused by mutations localized at chromosome 2q22--q23. We have analyzed a de novo translocation breakpoint at 2q22 in one patient presenting with this syndrome, and identified a gene, SIP1, which is disrupted by this chromosomal rearrangement. SIP1 encodes Smad interacting protein 1, a new member of the delta EF1/Zfh-1 family of two-handed zinc finger/homeodomain transcription factors. We determined the genomic structure and expression of the human SIP1 gene. Further analysis of four independent patients showed that SIP1 is altered by heterozygous frameshift mutations causing early truncation of the protein. SIP1, among other functions, seems to play crucial roles in normal embryonic development of neural structures and neural crest. Its deficiency, in altering function of the TGF beta/BMP/Smad-mediated signalling cascade, is consistent with some of the dysmorphic features observed in this syndrome, in particular the enteric nervous system defect that underlies HD.
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PMID:Loss-of-function mutations in SIP1 Smad interacting protein 1 result in a syndromic Hirschsprung disease. 1144 42

Tuberous Sclerosis Complex (TSC) is an autosomal dominant disorder associated with mutations in TSC1, which codes for hamartin, or TSC2, which codes for tuberin. The brain is one of the most severely affected organs, and CNS lesions include cortical tubers and subependymal giant cell astrocytomas, resulting in mental retardation and seizures. Tuberin and hamartin function together as a complex in mammals and Drosophila. We report here the association of Pam, a protein identified as an interactor of Myc, with the tuberin-hamartin complex in the brain. The C terminus of Pam containing the RING zinc finger motif binds to tuberin. Pam is expressed in embryonic and adult brain as well as in cultured neurons. Pam has two forms in the rat CNS, an approximately 450-kDa form expressed in early embryonic stages and an approximately 350-kDa form observed in the postnatal period. In cortical neurons, Pam co-localizes with tuberin and hamartin in neurites and growth cones. Although Pam function(s) are yet to be defined, the highly conserved Pam homologs, HIW (Drosophila) and RPM-1 (Caenorhabditis elegans), are neuron-specific proteins that regulate synaptic growth. Here we show that HIW can genetically interact with the Tsc1.Tsc2 complex in Drosophila and could negatively regulate Tsc1.Tsc2 activity. Based on genetic studies, HIW has been implicated in ubiquitination, possibly functioning as an E3 ubiquitin ligase through the RING zinc finger domain. Therefore, we hypothesize that Pam, through its interaction with tuberin, could regulate the ubiquitination and proteasomal degradation of the tuberin-hamartin complex particularly in the CNS.
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PMID:Pam and its ortholog highwire interact with and may negatively regulate the TSC1.TSC2 complex. 1455 97

We report a girl who had Hirschsprung disease in association with distinct facial appearance, microcephaly, agenesis of the corpus callosum and mental retardation (Mowat-Wilson syndrome). Mutation analysis of the zinc finger homeo box 1 B (ZFHX1 B) gene revealed a de novo 7 bp deletion (TGGCCCC) at nucleotide 1773 (1773 delTGGCCCC) resulting in a frameshift and leading to a termination codon at amino acid residue 604 (604 X) in exon 8 C. The zinc finger homeo box 1 B (Smad interacting protein-1) is a transcription corepressor of Smad target genes with functions in the patterning of neural crest derived cells, CNS, and midline structures. Mutations in ZFHX1 B can lead to neurological disorders in addition to dysmorphic features, megacolon, and other malformations.
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PMID:Frameshift mutation of the zinc finger homeo box 1 B gene in syndromic corpus callosum agenesis (Mowat-Wilson syndrome). 1468 59


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