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 a frequent cause of mental retardation resulting from the absence of FMRP, the protein encoded by the FMR1 gene. FMRP is an RNA-binding protein of unknown function which is associated with ribosomes. To gain insight into FMRP function, we performed immunolocalization analysis of FMRP truncation and fusion constructs which revealed a nuclear localization signal (NLS) in the amino terminus of FMRP as well as a nuclear export signal (NES) encoded by exon 14. A 17 amino acid peptide containing the FMRP NES, which closely resembles the NES motifs recently described for HIV-1 Rev and PKI, is sufficient to direct nuclear export of a microinjected protein conjugate. Sucrose gradient analysis shows that FMRP ribosome association is RNA-dependent and FMRP is found in ribonucleoprotein (RNP) particles following EDTA treatment. These data are consistent with nascent FMRP entering the nucleus to assemble into mRNP particles prior to export back into the cytoplasm and suggests that fragile X syndrome may result from altered translation of transcripts which normally bind to FMRP.
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PMID:The fragile X mental retardation protein is a ribonucleoprotein containing both nuclear localization and nuclear export signals. 884 25

Human cytomegalovirus (CMV) infection can be life threatening in the immune compromised and is associated with congenital defects and / or mental retardation in the neonate. The demonstrated association between CMV infection and rheumatoid factor (RF) raised the possibility of an induction of an autoimmune response upon vaccination with a candidate CMV vaccine, glycoprotein gB (UL55). The antibody responses generated after injections of an adenovirus-gB construct (Ad-gB) were studied in autoimmune-prone (MRL/mpj) and normal (BALB.k, C3H, and BALB/c) mice. Enzyme-linked immunosorbent assay and immunoblot analyses were done to identify the autoantibodies produced following immunization. Immunization with Ad-gB induced a significant IgG anti-viral response in all strains tested (p < 0.0001) compared to phosphate-buffered saline or HeLa controls. Ad-gB induced a significant IgG autoantibody response (p > 0.005) to the U1-70 kDa spliceosome protein in both autoimmune and normal strains whereas immunization with recombinant human La/SS-B did not. Autoantibodies to U1-70 kDa are part of the anti-ribonucleoprotein response seen in systemic lupus erythematosus and mixed connective tissue disease. Low levels of IgG RF and anti-double-stranded DNA antibodies were also induced. This study raises concern that immunization with CMV gB in individuals genetically predisposed to autoimmunity could trigger the development or acceleration of an autoimmune disease.
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PMID:Recombinant cytomegalovirus glycoprotein gB (UL55) induces an autoantibody response to the U1-70 kDa small nuclear ribonucleoprotein. 1055 20

The loss of FMR1 expression due to trinucleotide repeat expansion leads to fragile X syndrome, a cause of mental retardation. The encoded protein, FMRP, is a member of a gene family that also contains the fragile X-related proteins, FXR1P and FXR2P. FMRP has been shown to be a nucleocytoplasmic shuttling protein that selectively binds a subset of mRNAs, forms messenger ribonucleoprotein (mRNP) complexes, and associates with translating ribosomes. Here we describe a cell culture system from which we can isolate epitope-tagged FMRP along with mRNA, including its own message, and at least six other proteins. We identify two of these proteins as FXR1P and FXR2P by using specific antisera and identify a third protein as nucleolin by using mass spectrometry. The presence of nucleolin is confirmed by both reactivity with a specific antiserum as well as reverse coimmunoprecipitation where antinucleolin antiserum immunoprecipitates endogenous FMRP from both cultured cells and mouse brain. The identification of nucleolin, a known component of other mRNPs, adds a new dimension to the analysis of FMRP function, and the approach described should also allow the identification of the remaining unknown proteins of this FMRP-associated mRNP as well as the other bound mRNAs.
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PMID:Isolation of an FMRP-associated messenger ribonucleoprotein particle and identification of nucleolin and the fragile X-related proteins as components of the complex. 1056 18

The fragile-X syndrome is a mental disorder caused by the absence of FMRP (the Fragile-X Mental Retardation Protein). While FMRP is found to be associated with the ribosomal components, its precise translational function remains to be defined. Here we report that FMRP is not found with the abundant free polysomes of the reticulocyte lysate, but rather with a heavy ribonucleoprotein complex sedimenting over 400S. This unusual distribution of FMRP at an advanced stage of mammalian erythropoiesis may unveil the discrete role of FMRP in translation.
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PMID:A distinct FMRP polysomal population at an advanced stage of mammalian erythropoiesis. 1096 11

The absence of the fragile X mental retardation protein (FMRP), encoded by the FMR1 gene, is responsible for pathologic manifestations in the Fragile X Syndrome, the most frequent cause of inherited mental retardation. FMRP is an RNA-binding protein associated with polysomes as part of a messenger ribonucleoprotein (mRNP) complex. Although its function is poorly understood, various observations suggest a role in local protein translation at neuronal dendrites and in dendritic spine maturation. We present here the identification of CYFIP1/2 (Cytoplasmic FMRP Interacting Proteins) as FMRP interactors. CYFIP1/2 share 88% amino acid sequence identity and represent the two members in humans of a highly conserved protein family. Remarkably, whereas CYFIP2 also interacts with the FMRP-related proteins FXR1P/2P, CYFIP1 interacts exclusively with FMRP. FMRP--CYFIP interaction involves the domain of FMRP also mediating homo- and heteromerization, thus suggesting a competition between interaction among the FXR proteins and interaction with CYFIP. CYFIP1/2 are proteins of unknown function, but CYFIP1 has recently been shown to interact with the small GTPase Rac1, which is implicated in development and maintenance of neuronal structures. Consistent with FMRP and Rac1 localization in dendritic fine structures, CYFIP1/2 are present in synaptosomal extracts.
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PMID:A highly conserved protein family interacting with the fragile X mental retardation protein (FMRP) and displaying selective interactions with FMRP-related proteins FXR1P and FXR2P. 1143 99

The clinical features of the Fragile X mental retardation syndrome are linked to the absence of the set of protein isoforms, derived from alternative splicing of the Fragile X mental retardation gene 1 (FMR1), and collectively termed FMRP. FMRP is an RNA binding protein that is part of a ribonucleoprotein particle associated to actively translating polyribosomes, and which can shuttle between nucleus and cytoplasm. Two highly homologous human proteins, FXR1P and FXR2P, share the same domain structure as FMRP, and probably similar functions. The properties of FMRP suggested that it is involved in nuclear export, cytoplasmic transport, and/or translational control of target mRNAs. In particular, it may play a role in regulation of protein synthesis at postsynaptic sites of dendrites, and in maturation of dendritic spines. Efforts are underway to identify the putative specific mRNA targets of FMRP, and study the effect of FMRP absence on the corresponding proteins. Other approaches have led to the identification of proteins that interact with FMRP. Some of them discriminate between FMRP and the homologous FXR1/2P proteins, and may thus be important for defining unique functions of FMRP that are deficient in Fragile X patients. The physiological functions of FMRP are notably approached through the study of a FMR1 knock-out mouse model. The recent identification in Drosophila melanogaster of genes encoding homologs of FMRP/FXRP and of their interacting proteins, open the way to use of Drosophila genetics to study FMRP function.
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PMID:The Fragile X mental retardation protein. 1171 75

Transcription factors have traditionally been viewed as the main determinants of gene expression. Yet, in recent years it has become apparent that RNA-binding proteins also play a critical role in determining the levels of expression of a large number of genes. Once mRNAs are transcribed, RNA-binding proteins can control all subsequent steps in their function, from alternative splicing and translation to mRNA transport and stability. In the nervous system, a large number of genes are regulated post-transcriptionally via the interaction of their mRNAs with specific RNA-binding proteins. This type of regulation is particularly important in the control of the temporal and spatial pattern of gene expression during neural development. This review will discuss the function of the embryonic lethal abnormal vision (ELAV)/Hu family of nervous system-specific RNA-binding proteins, with a special emphasis on HuD, a member of this family that controls GAP-43 mRNA stability and expression. In addition, we will present recent findings on other neural RNA-binding proteins: the ribonucleoprotein K homology (KH)-domain proteins, Fragile X mental retardation protein (FMRP), quakinguiable protein (QKI), and Nova-1. Together with the ELAV/Hu family, these proteins are essential for proper neural development and in some cases for plasticity in the mature brain. The biological significance of these proteins is evident not only by their evolutionary conservation but also by the magnitude of problems arising from autoimmune reactions against them or from mutations affecting their expression or function.
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PMID:Role of HuD and other RNA-binding proteins in neural development and plasticity. 1194 57

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

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

Spinal muscular atrophy (SMA) is a common neurodegenerative disease that is caused by deletions or loss-of-function mutations in the Survival of Motor Neuron (SMN) protein. SMN is part of a large complex that functions in the assembly/restructuring of ribonucleoprotein (RNP) complexes. We recently showed in HeLa cells that two components of the SMN complex, Gemin3 and Gemin4, together with the argonaute protein eIF2C2, also associate with microRNAs (miRNAs) as part of a novel class of RNPs termed miRNPs. Here we report on miRNPs isolated from neuronal cell lines of mouse and human, and describe 53 novel miRNAs. Several of these miRNAs are conserved in divergent organisms, including rat, zebrafish, pufferfish, and the nematode Caenorhabditis elegans. The chromosomal locations of most of the novel miRNAs were identified and indicate some phylogenetic conservation of the likely precursor structures. Interestingly the gene locus of one miRNA, miR-175, is a candidate region for two neurologic diseases: early-onset parkinsonism (Waisman syndrome) and X-linked mental retardation (MRX3). Also, several miRNAs identified as part of miRNPs in these cells appear to constitute two distinct subfamilies. These subfamilies comprise multiple copies of miRNAs on different chromosomes, suggesting an important function in the regulation of gene expression.
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PMID:Numerous microRNPs in neuronal cells containing novel microRNAs. 1255 60


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