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)

The Rubinstein-Taybi syndrome (RTS) is a well-defined syndrome with facial abnormalities, broad thumbs, broad big toes and mental retardation as the main clinical features. Many patients with RTS have been shown to have breakpoints in, and microdeletions of, chromosome 16p13.3 (refs 4-8). Here we report that all these breakpoints are restricted to a region that contains the gene for the human CREB binding protein (CBP), a nuclear protein participating as a co-activator in cyclic-AMP-regulated gene expression. We show that RTS results not only from gross chromosomal rearrangements of chromosome 16p, but also from point mutations in the CBP gene itself. Because the patients are heterozygous for the mutations, we propose that the loss of one functional copy of the CBP gene underlies the developmental abnormalities in RTS and possibly the propensity for malignancy.
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PMID:Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP. 763 Mar 90

Several human inherited diseases have been localized to the Xq13.3 region of the human X chromosome (X-linked dystonia with Parkinsonism, sideroblastic anemia, SCID, Menkes disease and X-linked mental retardation loci). Genes involved in the phenotypes have been isolated for only two of them (Menkes and SCIDX). It was therefore interesting to isolate and characterize new genes from the region. In a previous work (12 and Consalez et al, in preparation) we isolated a gene (XNP), located 350 Kb proximal to PGK1, potentially coding for a nuclear protein. We describe here the cloning and characterization of the murine homologue. The pattern of expression of the gene in the newborn mouse (especially the expression in particular regions of the brain: optical lobe, frontal cortex, hippocampus and cerebellum), as well as the expression in human tissues, suggests that this gene might be involved in neuronal differentiation. Among the different morbid phenotypes assigned to the region, X-linked mental retardation would be the best candidate to be associated with this gene.
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PMID:Cloning and expression of the murine homologue of a putative human X-linked nuclear protein gene closely linked to PGK1 in Xq13.3. 816 50

FMR2 is the gene associated with FRAXE mental retardation. It is expressed as an 8.7-kb transcript in placenta and adult brain. A fetal-specific FMR2 transcript of approximately 12 kb was detected in fetal brain and at a lower level in fetal lung and kidney. FMR2 is a large gene composed of 22 exons spanning at least 500 kb on Xq28. Alternative splicing involving exons 2, 3, 5, 7, and 21 was not tissue specific as tested on mRNA from human fetal and infant brain. FMR2 is translated into a 1311-amino-acid nuclear protein with putative transcription transactivation potential. Subcellular localization studies with green fluorescent protein as a reporter show that both nuclear addresses found in the FMR2 sequence are functional and direct the FMR2 protein into the nucleus. FMR2 together with AF4 and LAF4 forms a new family of nuclear proteins with DNA-binding capacity and transcription transactivation potential. BLAST searches of the dbEST database revealed the presence of at least two other groups of nonoverlapping ESTs showing high similarity to the FMR2-related family of proteins. One of them, represented by the EST W26686, maps to chromosome 5q31. Amino acid similarity among the proteins encoded by members of the gene family is high in the NH2 terminus, low in the middle, and high again in the COOH end. Available information from members of the family shows that genomic organization is conserved. This FMR2-related gene family encodes nuclear proteins with involvement in mental retardation (FMR2), cancer (AF4), and lymphocyte differentiation (LAF4) or with unknown function (EST W26686 and/or AA025630).
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PMID:Gene structure and subcellular localization of FMR2, a member of a new family of putative transcription activators. 929 37

The transcriptional silencing of the FMR2 gene has been implicated in FRAXE mental retardation. FRAXE individuals have been shown to exhibit learning deficits, including speech delay, reading and writing problems. FMR2 encodes a large protein of 1311 amino acids and is a member of a gene family encoding proline-serine-rich proteins that have properties of nuclear transcription factors. To characterize the expression of the fragile X mental retardation 2 (FMR2) protein, polyclonal antibodies were raised against two regions of the human FMR2 protein and used in immunofluorescence experiments on mouse brain cryosections. Our results demonstrate for the first time that the FMR2 protein is localized in neurons of the neocortex, Purkinje cells of the cerebellum and the granule cell layer of the hippocampus. FMR2 staining is shown to colocalize with the nuclear stain 4,6-diamidino-2-phenylindole (DAPI) confirming that FMR2 is a nuclear protein. The localization of FMR2 protein to the mammalian hippocampus and other brain structures involved with cognitive function is consistent with the learning deficits seen in FRAXE individuals.
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PMID:Localization of the fragile X mental retardation 2 (FMR2) protein in mammalian brain. 1065 94

Rubinstein-Taybi syndrome (RTS) is a malformation syndrome characterised by facial abnormalities, broad thumbs, broad big toes, and mental retardation. In a subset of RTS patients, microdeletions, translocations, and inversions involving chromosome band 16p13.3 can be detected. We have previously shown that disruption of the human CREB binding protein (CREBBP or CBP) gene, either by these gross chromosomal rearrangements or by point mutations, leads to RTS. CBP is a large nuclear protein involved in transcription regulation, chromatin remodelling, and the integration of several different signal transduction pathways. Here we report diagnostic analysis of CBP in 194 RTS patients, divided into several subsets. In one case the mother is also suspect of having RTS. Analyses of the entire CBP gene by the protein truncation test showed 4/37 truncating mutations. Two point mutations, one 11 bp deletion, and one mutation affecting the splicing of the second exon were detected by subsequent sequencing. Screening the CBP gene for larger deletions, by using different cosmid probes in FISH, showed 14/171 microdeletions. Using five cosmid probes that contain the entire gene, we found 8/89 microdeletions of which 4/8 were 5' or interstitial. This last subset of microdeletions would not have been detected using the commonly used 3' probe RT1, showing the necessity of using all five probes.
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PMID:Diagnostic analysis of the Rubinstein-Taybi syndrome: five cosmids should be used for microdeletion detection and low number of protein truncating mutations. 1069 51

Members of the AF4/FMR2 family of nuclear proteins are involved in human diseases such as acute lymphoblastic leukemia and mental retardation. Here we report the identification and characterization of the Drosophila lilliputian (lilli) gene, which encodes a nuclear protein related to mammalian AF4 and FMR2. Mutations in lilli suppress excessive neuronal differentiation in response to a constitutively active form of Raf in the eye. In the wild type, Lilli has a partially redundant function in the Ras/MAPK pathway in differentiation but it is essential for normal growth. Loss of Lilli function causes an autonomous reduction in cell size and partially suppresses the increased growth associated with loss of PTEN function. These results suggest that Lilli acts in parallel with the Ras/MAPK and the PI3K/PKB pathways in the control of cell identity and cellular growth.
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PMID:Lilliputian: an AF4/FMR2-related protein that controls cell identity and cell growth. 1117 3

Mecp2 is an X-linked gene encoding a nuclear protein that binds specifically to methylated DNA (ref. 1) and functions as a general transcriptional repressor by associating with chromatin-remodeling complexes. Mecp2 is expressed at high levels in the postnatal brain, indicating that methylation-dependent regulation of gene expression may have a crucial role in the mammalian central nervous system. Consistent with this notion is the recent demonstration that MECP2 mutations cause Rett syndrome (RTT, MIM 312750), a childhood neurological disorder that represents one of the most common causes of mental retardation in females. Here we show that Mecp2-deficient mice exhibit phenotypes that resemble some of the symptoms of RTT patients. Mecp2-null mice were normal until 5 weeks of age, when they began to develop disease, leading to death between 6 and 12 weeks. Mutant brains showed substantial reduction in both weight and neuronal cell size, but no obvious structural defects or signs of neurodegeneration. Brain-specific deletion of Mecp2 at embryonic day (E) 12 resulted in a phenotype identical to that of the null mutation, indicating that the phenotype is caused by Mecp2 deficiency in the CNS rather than in peripheral tissues. Deletion of Mecp2 in postnatal CNS neurons led to a similar neuronal phenotype, although at a later age. Our results indicate that the role of Mecp2 is not restricted to the immature brain, but becomes critical in mature neurons. Mecp2 deficiency in these neurons is sufficient to cause neuronal dysfunction with symptomatic manifestation similar to Rett syndrome.
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PMID:Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice. 1124 18

A growing number of human disorders have been associated with expansions of a tract of a single amino acid. Recently, polyalanine (polyA) tract expansions in the Aristaless-related homeobox (ARX) protein have been identified in a subset of patients with infantile spasms and mental retardation. How alanine expansions in ARX, or any other transcription factor, cause disease have not been determined. We generated a series of polyA expansions in Arx and expressed these in cell culture and brain slices. Transfection of these constructs results in nuclear protein aggregation, filamentous nuclear inclusions, and an increase in cell death. These inclusions are ubiquitinated and recruit Hsp70. Coexpressing Hsp70 decreases the percentage of cells with nuclear inclusions. Finally, we show that expressing mutant Arx in mouse brains results in neuronal nuclear inclusion formation. Our data suggest expansions in one of the ARX polyA tracts results in nuclear protein aggregation and an increase in cell death; likely underlying the pathogenesis of the associated infantile spasms and mental retardation.
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PMID:A polyalanine tract expansion in Arx forms intranuclear inclusions and results in increased cell death. 1553 98

Methyl-CpG binding protein 2 gene (MECP2), the gene implicated in Rett syndrome, was also reported to be involved in mental retardation and autism. MECP2, MBD1, MBD2, MBD3, and MBD4 comprise a nuclear protein family sharing the methyl-CpG binding domain (MBD) and are related to transcriptional repression. In 65 Japanese autistic patients, all the exons of each gene were screened for mutations by DHPLC, and the results were confirmed by direct sequencing. An R269C mutation that resulted in the addition of cysteine near a cysteine rich region was found in the MBD1 gene in one patient. This mutation was also detected in the patient's father with some phenotypes of autism and his normal sister, but not in 151 controls. Two repeat length polymorphisms, (GGGGCC)2 to 3 and (GGC)4 to 5, were detected in MBD2, and several polymorphisms were detected in each gene. Although our findings could not confirm that the genes of this family are responsible for the etiology in the majority of autistic patients, the R269C mutation in the MBD1 gene may relate to autism. The potential association of the high-polymorphic gene variants with autism needs to be studied further. Furthermore, these polymorphisms are useful for linkage analysis.
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PMID:Mutation analysis of methyl-CpG binding protein family genes in autistic patients. 1596 18

Down's syndrome (DS) or trisomy 21 is the most frequent genetic birth defect associated with mental retardation. Although DS has been known for more than a 100 years and its chromosomal basis recognized for half a century (1959), the underlying patho-mechanisms for the phenotype formation remain elusive and cannot be fully explained by simple gene dosage effect. The general consensus is that the extra chromosome 21 genes perturb the global metabolism of the body cells. Our experiments show that the most prominent metabolic perturbation occurs during ribosome biogenesis in the cells of DS babies/infants. In humans, ribosomal RNA (rRNA) gene families or nucleolar organizer regions (NORs) are localized at the secondary constriction (on the satellite stalks) of five pairs of acrocentric chromosomes (13, 14, 15, 21 and 22) and their activities are evaluated specifically either in metaphase or interphase through a procedure known as AgNOR or silver staining. Our successive AgNOR studies, supported by RNA and nuclear protein measurement, show that cells from DS infants produce more ribosomes than expected, accounting for the extra set of active rRNA gene family (1/6-1/11) situated on the extra chromosome 21. Thus, the presence of an extra chromosome 21 stimulates a global increase in ribosome biogenesis in cooperation with other NOR-bearing chromosomes, causing unnecessary rRNA and ribosomal proteins synthesis compared to controls. Following the description of NORs, AgNOR, AgNOR-proteins, AgNOR measurement and our experimental results, we propose that the extra RNA and protein synthesis can cause a fundamental handicap to DS infants, contributing to the formation of DS phenotypes, due to the wasted energy in producing unnecessary macromolecules, including energy (GTP)-dependent transport of the excessive ribosomes from the nucleus to the cytoplasm.
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PMID:AgNOR status in Down's syndrome infants and a plausible phenotype formation hypothesis. 1933 89


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