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)

Fragile X syndrome is one of the most common forms of inherited mental retardation. In most cases the disease is caused by the methylation-induced transcriptional silencing of the fragile X mental retardation 1 (FMR1) gene that occurs as a result of the expansion of a CGG repeat in the gene's 5'UTR and leads to the loss of protein product fragile X mental retardation protein (FMRP). FMRP is an RNA binding protein that associates with translating polyribosomes as part of a large messenger ribonucleoprotein (mRNP) and modulates the translation of its RNA ligands. Pathological studies from the brains of patients and from Fmr1 knockout mice show abnormal dendritic spines implicating FMRP in synapse formation and function. Evidence from both in vitro and in vivo neuronal studies indicates that FMRP is located at the synapse and the loss of FMRP alters synaptic plasticity. As synaptic plasticity has been implicated in learning and memory, analysis of synapse abnormalities in patients and Fmr1 knockout mice should prove useful in studying the pathogenesis of fragile X syndrome and understanding learning and cognition in general. If an appreciable portion of the total variance (in IQ) is due to sex linked genes, it is of more importance that a boy should have a clever mother than a clever father. Hogben 1932 (quoted in Lehrke 1974)
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PMID:A decade of molecular studies of fragile X syndrome. 1205 12

The fragile X mental retardation syndrome is caused by large methylated expansions of a CGG repeat in the FMR1 gene that lead to the loss of expression of FMRP, an RNA-binding protein. FMRP is proposed to act as a regulator of mRNA transport or translation that plays a role in synaptic maturation and function. The recent observations of unexpected phenotypes in some carriers of fragile X premutations suggest a pathological role, in these individuals, of an abnormal FMR1 mRNA. FMRP was recently shown to interact preferentially with mRNAs containing a G quartet structure. Mouse and Drosophila models are used to decipher the function of FMRP, which was found to inhibit translation of some mRNA targets, but may be stimulatory in other cases. Proteins interacting with FMRP have been identified, and suggest a link with the Rac1 GTPase pathway that is important in neuronal maturation. Recent advances also include identification of other genes implicated in X-linked mental retardation.
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PMID:Advances in understanding of fragile X pathogenesis and FMRP function, and in identification of X linked mental retardation genes. 1207 71

Fragile X syndrome, the most common form of inherited mental retardation, is caused by loss-of-function mutations in the fragile X mental retardation 1 (fmr1) gene. FMR1 is an RNA binding protein that is highly expressed in neurons of the central nervous system. Recent studies in Drosophila indicate that FMR1 plays an important role in synaptogenesis and axonal arborization, which may underlie the observed deficits in flight ability and circadian behavior of fmr1 mutant flies. The relevance of these studies to our understanding of fragile X syndrome is discussed.
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PMID:Understanding fragile X syndrome: insights from retarded flies. 1208 33

Fragile X syndrome (FraX) is one of the most prevalent genetic causes of mental retardation. FraX is associated with an unstable expansion of a polymorphism within the 5' untranslated region of the FMR1 gene. The main consequence of this mutation is a reduction in the levels of the gene product (FMRP). FMRP is an RNA-binding protein with multiple spliced variants (isoforms) and high levels of expression in a variety of tissues, including neurons. In the latter cells, it is localized not only to the perikaryon but also to dendrites and dendritic spines. FMRP belongs to a family of proteins that includes the Fragile X Related Proteins or FXRPs. FXRPs share high homology in their functional domains with FMRP, and also associate with mRNA and components of the protein synthesis apparatus. However, FXRPs do not have the same temporo-spatial pattern of distribution (and other properties) of FMRP. Immunochemical assays have confirmed that a functionally uncompensated FMRP deficit is the essence of the FraX molecular phenotype. Here, we report our preliminary study on FXRPs levels in leukocytes from FraX males. By immunoblotting, we found that a marked reduction in FMRP levels is associated with a modest increase in FXR1P and no changes in FXR2P levels. The consequences of this reduced FMRP expression on protein synthesis, in other words, the identification of FMRP targets, can be studied by different molecular approaches including protein interaction and proteomics methods. By two-dimensional gel electrophoresis, we showed that in FraX leukocytes there is a defect in acetylation that involves prominently the regulatory protein annexin-1. Extension of current studies of the molecular phenotype to more brain-relevant tissue samples, a wider range of proteomics-based methods, and correlative analyses of FMRP homologues and FMRP targets with multiple behavioral measures, will greatly expand our understanding of FraX pathogenesis and it will help to develop and monitor new therapeutic strategies.
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PMID:Molecular phenotype of Fragile X syndrome: FMRP, FXRPs, and protein targets. 1211 48

Fragile X mental retardation results from the absence of a selective RNA-binding protein, FMRP. Previous studies demonstrated that FMRP forms messenger ribonucleoprotein (mRNP) complexes to associate with translating polyribosomes, suggesting that FMRP is involved in regulating protein synthesis. We are now facing the changing questions: How does FMRP influence protein synthesis in the brain? What is the target for FMRP in learning and memory? How does the absence of FMRP cause misregulation of protein synthesis, which in turn leads to mental impairment in fragile X syndrome? Models for abnormal neuronal function as a result of misregulated translation due to the absence of FMRP are discussed.
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PMID:Fragile X mental retardation: misregulation of protein synthesis in the developing brain? 1211 49

Fragile X syndrome linked to the FRAXA locus is the most common inherited genetic disease accounting for mental retardation and is usually caused by the expansion of an unstable CGG repeat in the first exon of the FMR1 gene on the X chromosome. Despite its robustness, Southern blot is not suitable for large-scale routine screening as part of neuropediatric practice. PCR appears as an interesting alternative, and various protocols have been successfully applied to molecular screening in mentally retarded boys and girls. Unfortunately, as of this date these protocols are unable to detect the expanded allele in FRAXA females reliably, thereby failing to discriminate between fully mutated females from normal homozygotes. Therefore, we opted for an alternative approach in designing a semiquantitative PCR assay, based on the amplification of the sole wild-type allele. This method allowed us to detect the presence of one or two normal alleles with the same sizes, thereby discriminating between a FRAXA fully mutated female or a normal homozygote, respectively. A trial on 95 DNA samples from normal and mutated females demonstrated the reliability of the procedure. We believe this simple PCR assay is a powerful approach that would reduce the recourse to Southern blotting in females with mental retardation of unknown etiology.
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PMID:Simple fluorescent PCR assay for discriminating FRAXA fully mutated females from normal homozygotes. 1221 55

Fragile X syndrome is the most common inherited form of mental retardation. Although this syndrome originates from the absence of the RNA-binding protein FMRP, the molecular mechanisms underlying the cognitive deficits are unknown. The expression pattern of 6789 genes was studied in the brains of wild-type and FMR1 knockout mice, a fragile X syndrome animal model that has been associated with cognitive deficits. Differential expression of more than two-fold was observed for the brain mRNA levels of 73 genes. Differential expression of nine of these genes was confirmed by real-time quantitative reverse transcription-polymerase chain reaction and by in situ hybridization. In addition to corroborating the microarray data, the in situ hybridization analysis showed distinct spatial distribution patterns of microtubule-associated protein 2 and amyloid beta precursor protein. A number of differentially expressed genes associated with the fragile X syndrome phenotype have been previously involved in other memory or cognitive disorders.
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PMID:Gene expression profiles in a transgenic animal model of fragile X syndrome. 1227 Jun 84

FMRP belongs to a family of widely expressed proteins that contain RNA-binding domains. Although lack of human FMRP results in mental retardation, correlated with subtle synaptic changes, the precise role of FMRP remains elusive. The Drosophila genome contains a single gene homologous to the FXR family. We show that dFMR1 is subjected to transcriptional and posttranscriptional regulation during development and that it homomerizes, like its human counterpart. dFMR1 profile of expression recapitulates that of the human FXR protein family: it is highly enriched in muscles, in central nervous system and in gonads. In the larval brain, anti-dFMR1 also recognizes mushroom bodies, a centre that mediates learning and memory. These features make the fly an ideal system to analyse the role of the FXR family and to identify genes in the FMRP pathway.
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PMID:Novel features of dFMR1, the Drosophila orthologue of the fragile X mental retardation protein. 1246 May 46

This review covers the history and nosology of X-linked mental retardation (XLMR) in which the following, largely clinically based, subclassification was used: fragile X syndrome (FRAXA), syndromic forms (MRXS) and non-specific forms (MRX). After the discovery of the FMR2 gene at the FRAXE site, 10 MRX genes have been identified in the last 6 years. A short description is given of the strategies used to identify the genes that cause mental retardation (MR). Furthermore, their potential functions and the association with MR will be discussed. It is emphasized that mutations in several of these MR genes can result in non-specific, as well as in syndromic forms of XLMR. Present findings stress the importance of accurate clinical evaluation. Most considerably, genotype-phenotype correlation studies of affected individuals in XLMR families with MRX gene mutations are necessary to define the criteria of MRX vs MRXS subclassification.
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PMID:X-linked mental retardation: vanishing boundaries between non-specific (MRX) and syndromic (MRXS) forms. 1248 86

The Fragile X mental retardation gene (FMR1) contains a polymorphic trinucleotide CGG repeat in the 5' untranslated region (UTR) of the FMR1 messenger. We have characterized three lymphoblastoid cell lines derived from unrelated male carriers of a premutation that overexpress FMR1 mRNA and show reduced FMRP level compared to normal cells. The analysis of polysomes/mRNPs distribution of mRNA in the cell lines with a premutation shows that the polysomal association of FMR1 mRNA, which is high in normal cells, becomes progressively lower with increasing CGG repeat expansion. In addition, we could detect a very low level of FMR1 mRNA in a lymphoblastoid cell line from a patient with a full mutation. In this case, FMR1 mRNA is not at all associated with polysomes, in agreement with the complete absence of FMRP. The impairment of FMR1 mRNA translation in patients with the Fragile X syndrome with FMR1 premutation is the cause of the lower FMRP levels that leads to the clinical involvement.
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PMID:Reduced FMR1 mRNA translation efficiency in fragile X patients with premutations. 1251 81


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