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)

Expansion and methylation of CGG repeat sequences is associated with Fragile X syndrome in humans. We have examined the consequences of CGG repeat expansion and methylation for nucleosome assembly and positioning on the Fragile X Mental Retardation gene 1 (FMR1) gene. Short unmethylated CGG repeats are not particularly favored in terms of affinity for the histone octamer or for positioning of the reconstituted nucleosome. However, upon methylation their affinity for the histone octamer increases and a highly positioned nucleosome assembles with the repeat sequences found adjacent to the nucleosomal dyad. Expansion of these CGG repeats abolishes the preferential nucleosome assembly due to methylation. Thus, the expansion and methylation of these triplet repeats can alter the functional organization of chromatin, which may contribute to alterations in the expression of the FMR1 gene and the disease phenotype.
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PMID:Nucleosome assembly on methylated CGG triplet repeats in the fragile X mental retardation gene 1 promoter. 879 82

Mutation of FMR1 results in fragile X mental retardation. The most common FMR1 mutation is expansion of a CGG repeat tract at the 5' end of FMR1, which leads to cytosine methylation and transcriptional silencing. Both DNA methylation and histone deacetylation have been associated with transcriptional inactivity. The finding that the methyl cytosine-binding protein MeCP2 binds to histone deacetylases and represses transcription in vivo supports a model in which MeCP2 recruits histone deacetylases to methylated DNA, resulting in histone deacetylation, chromatin condensation and transcriptional silencing. Here we demonstrate that the 5' end of FMR1 is associated with acetylated histones H3 and H4 in cells from normal individuals, but acetylation is reduced in cells from fragile X patients. Treatment of fragile X cells with 5-aza-2'-deoxycytidine (5-aza-dC) resulted in reassociation of acetylated histones H3 and H4 with FMR1 and transcriptional reactivation, whereas treatment with trichostatin A (TSA) led to almost complete acetylated histone H4 and little acetylated histone H3 reassociation with FMR1, as well as no detectable transcription. Our results represent the first description of loss of histone acetylation at a specific locus in human disease, and advance understanding of the mechanism of FMR1 transcriptional silencing.
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PMID:Acetylated histones are associated with FMR1 in normal but not fragile X-syndrome cells. 1031 71

CBP (CREBBP/CREB-binding protein) and p300 are related signal-dependent transcriptional cofactors and histone acetyltransferases. They are both implicated in tumorigenesis and mutations in the human CBP gene have been found in Rubinstein-Taybi syndrome (RTS), which is characterized by multiple developmental defects and mental retardation. Studies with CBP and p300 mouse mutants indicate that both proteins are required for normal development, and that there is an essential gene dosage-sensitive role for these transcriptional cofactors in embryogenesis, cell differentiation and proliferation. Although it is generally believed that the expression of CBP and p300 is ubiquitous, we report here that they are developmentally regulated during mouse embryogenesis. In the developing CNS, CBP and p300 proteins were found throughout the newly formed neural plate, but their expression was later restricted to the dorsal parts of the developing neural tube. Later in neural development, CBP and p300 proteins could also be found in subsets of ventral neurons, including motor neurons and oligodendrocytes. During organogenesis, CBP and p300 proteins were expressed in specific cell types of the developing heart, vasculature, skin, lung and liver. Many of these tissues and organs are known to be affected in mutant mice lacking CBP and/or p300, and in RTS patients. Interestingly, while CBP and p300 proteins show extensive overlapping expression during mouse embryogenesis, we observed that their subcellular localization is developmentally regulated in several cell types. Taken together, our results suggest that there are common, as well as distinct, biochemical functions of CBP and p300 during mouse development.
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PMID:Developmentally regulated expression of the transcriptional cofactors/histone acetyltransferases CBP and p300 during mouse embryogenesis. 1061 21

Hypermethylation of the FMR1 promoter reduces its transcriptional activity, resulting in the mental retardation and macroorchidism characteristic of Fragile X syndrome. How exactly methylation causes transcriptional silencing is not known but is relevant if current attempts to reactivate the gene are to be successful. Understanding the effect of methylation requires a better understanding of the factors responsible for FMR1 gene expression. To this end we have identified five evolutionarily conserved transcription factor binding sites in this promoter and shown that four of them are important for transcriptional activity in neuronally derived cells. We have also shown that USF1, USF2, and alpha-Pal/Nrf-1 are the major transcription factors that bind the promoter in brain and testis extracts and suggest that elevated levels of these factors account in part for elevated FMR1 expression in these organs. We also show that methylation abolishes alpha-Pal/Nrf-1 binding to the promoter and affects binding of USF1 and USF2 to a lesser degree. Methylation may therefore inhibit FMR1 transcription not only by recruiting histone deacetylases but also by blocking transcription factor binding. This suggests that for efficient reactivation of the FMR1 promoter, significant demethylation must occur and that current approaches to gene reactivation using histone deacetylase inhibitors alone may therefore have limited effect.
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PMID:Interaction of the transcription factors USF1, USF2, and alpha -Pal/Nrf-1 with the FMR1 promoter. Implications for Fragile X mental retardation syndrome. 1105 4

The protein EP300 and its paralog CREBBP (CREB-binding protein) are ubiquitously expressed transcriptional co-activators and histone acetyl transferases. The gene EP300 is essential for normal cardiac and neural development, whereas CREBBP is essential for neurulation, hematopoietic differentiation, angiogenesis and skeletal and cardiac development. Mutations in CREBBP cause Rubinstein-Taybi syndrome, which is characterized by mental retardation, skeletal abnormalities and congenital cardiac defects. The CBP/p300-interacting transactivator with ED-rich tail 2 (CITED2) binds EP300 and CREBBP with high affinity and regulates gene transcription. Here we show that Cited2-/- embryos die with cardiac malformations, adrenal agenesis, abnormal cranial ganglia and exencephaly. The cardiac defects include atrial and ventricular septal defects, overriding aorta, double-outlet right ventricle, persistent truncus arteriosus and right-sided aortic arches. We find increased apoptosis in the midbrain region and a marked reduction in ErbB3-expressing neural crest cells in mid-embryogenesis. We show that CITED2 interacts with and co-activates all isoforms of transcription factor AP-2 (TFAP2). Transactivation by TFAP2 isoforms is defective in Cited2-/- embryonic fibroblasts and is rescued by ectopically expressed CITED2. As certain Tfap2 isoforms are essential in neural crest, neural tube and cardiac development, we propose that abnormal embryogenesis in mice lacking Cited2 results, at least in part, from its role as a Tfap2 co-activator.
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PMID:Cardiac malformations, adrenal agenesis, neural crest defects and exencephaly in mice lacking Cited2, a new Tfap2 co-activator. 1169 77

The present review on the pharmacological reactivation of inactive genes focuses on our experience with the fragile X syndrome. The fragile X syndrome of mental retardation is the prototype of a series of inherited neurological disorders caused by abnormal expansion of repeated trinucleotide sequences embedded in various genes. In a number of these disorders, such as Huntington disease and several forms of spinocerebellar ataxias, the expanded CAG repeat is translated, resulting in a polyglutamine-containing protein that indirectly causes neurodegeneration. On the contrary, in the fragile X syndrome, the expanded CGG repeat is contained in the regulatory region of the FMR1 gene and causes transcriptional inactivation. The mutation spares the coding region of the FMR1 gene, which potentially would allow synthesis of a normal protein if transcription could be restored. This prompted us to try and reactivate the gene function with different pharmacological regimens. We discuss our successful results with DNA demethylating and histone hyperacetylating drugs and their implications for future treatments of the fragile X syndrome.
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PMID:Pharmacological reactivation of inactive genes: the fragile X experience. 1171 76

Rett syndrome is a neurodevelopmental disorder of early postnatal brain growth in girls. Patients show a normal neonatal period with subsequent developmental regression and a loss of acquired skills (communication and motor skills), deceleration of head growth, and development of typical hand stereotypies. Recent studies have shown that mutations in the X-linked methyl CpG binding protein 2 gene (MeCP2) cause most typical cases of Rett syndrome. The MeCP2 gene encodes a protein that binds methylated cytosine residues of CpG dinucleotides and mediates, with histone deacetylases and transcriptional repressors, the transcription "silencing" of other genes. Girls with Rett syndrome exhibit mosaic expression for the MeCP2 defect at the cellular level, with most patients showing random X-inactivation and approximately equal numbers of cells expressing the normal MeCP2 gene and the mutated MeCP2 gene. In rare cases, females with a MeCP2 mutation escape phenotypic expression of the disorder because of nonrandom X-inactivation and the preferential inactivation of the mutated MeCP2 allele. Nonrandom patterns of X-inactivation may also contribute to the clinical variability often seen in girls with Rett syndrome. The spectrum of clinical phenotype caused by MeCP2 mutations is wide, including milder "preserved speech" variants, the severe congenital Rett variant, and a subset of X-linked recessive mental retardation in boys. Studies have shown that atypical and classical Rett syndrome can caused by the same MeCP2 mutations, indicating clinical phenotype is variable even among girls with the same MeCP2 mutation. The relationship between type of MeCP2 mutation, X-inactivation status, and clinical phenotype of Rett syndrome is complex and likely involves other environmental and polygenic modifiers.
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PMID:Associations between MeCP2 mutations, X-chromosome inactivation, and phenotype. 1211 35

RBBP7 is a highly conserved WD-repeat protein that interacts with histone deacetylases and is a component of several co-repressor complexes. The mouse gene Rbbp7 spans approximately 20 kb, consists of at least 12 exons, and contains a C/T polymorphism in the 3' splice acceptor region of intron 3. We found that Rbbp7 contains a TATA-less promoter with multiple transcription initiation sites. In transient transfection assays, we identified potential positive regulatory elements upstream of the proximal promoter at -668 to -1710. RBBP7 protein is detectable from at least day 9.5 of embryogenesis and is strongly expressed in the developing kidney and brain. Consistent with its association with co-repressor complexes, we demonstrate that RBBP7 represses the c-FOS transactivation domain in response to mitogen stimulation. We have also excluded human RBBP7 as a candidate gene in six patients that exhibit X-linked mental retardation, a heterogeneous developmental disorder that has been linked in some cases to mutations in genes involved in chromatin remodeling.
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PMID:Characterization of the gene encoding mouse retinoblastoma binding protein-7, a component of chromatin-remodeling complexes. 1237 95

Methyl-CpG-binding protein 2 is a characteristic member of the methyl-CpG-binding protein family of transcription regulators. In conjunction with Sin3, MeCP2 recruits class I histone deacetylases to methyl-CpG regions to suppress transcription. Rett syndrome, a disorder characterized by mental retardation and autistic features, is associated in a majority of cases with mutations within the coding region of the MeCP2 gene. Considering that defective MeCP2 has mainly been related to Rett syndrome and other neurologic manifestations, we examined methyl-CpG-binding protein 2 cellular and subcellular compartmentalization in normal brain by immunochemical methods. Methyl-CpG-binding protein 2 immunoreactivity is present mainly in neurons; while the few immunostained glia show label confined to nuclei, many neurons also show slight perikaryal staining. Using well-characterized tissue fractions, we found that methyl-CpG-binding protein 2 but not Sin3 is found in both nuclear and postsynaptic compartments. This novel extranuclear localization is not unique to methyl-CpG-binding protein 2, since it has been previously reported for other transcription regulators such as c-Fos. These findings support the concept that methyl-CpG-binding protein 2 may link synaptic activity and transcriptional regulation in neurons.
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PMID:Methyl-CpG-binding protein 2 is localized in the postsynaptic compartment: an immunochemical study of subcellular fractions. 1253 40

Syndromes of disordered 'chromatin remodeling' are unique in medicine because they arise from a general deregulation of DNA transcription caused by mutations in genes encoding enzymes which mediate changes in chromatin structure. Chromatin is the packaged form of DNA in the eukaryotic cell. It consists almost entirely of repeating units, called nucleosomes, in which short segments of DNA are wrapped tightly around a disk-like structure comprising two subunits of each of the histone proteins H2A, H2B, H3 and H4. Histone proteins are covalently modified by a number of different adducts (i.e. acetylation and phosphorylation) that regulate the tightness of the DNA-histone interactions. Mutations in genes encoding enzymes that mediate chromatin structure can result in a loss of proper regulation of chromatin structure, which in turn can result in deregulation of gene transcription and inappropriate protein expression. In this review we present examples of representative genetic diseases that arise as a consequence of disordered chromatin remodeling. These include: alpha-thalassemia/mental retardation syndrome, X-linked (ATR-X); Rett syndrome (RS); immunodeficiency-centromeric instability-facial anomalies syndrome (ICF); Rubinstein-Taybi syndrome (RSTS); and Coffin-Lowry syndrome (CLS).
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PMID:Syndromes of disordered chromatin remodeling. 1285 1


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