Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917816 (mental retardation)
 15,867 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Functional absence of fragile X mental retardation protein (FMRP) causes the fragile X syndrome, a hereditary form of mental retardation characterized by a change in dendritic spine morphology. The RNA-binding protein FMRP has been implicated in regulating postsynaptic protein synthesis. Here we have analyzed whether the abundance of scaffold proteins and neurotransmitter receptor subunits in postsynaptic densities (PSDs) is altered in the neocortex and hippocampus of FMRP-deficient mice. Whereas the levels of several PSD components are unchanged, concentrations of Shank1 and SAPAP scaffold proteins and various glutamate receptor subunits are altered in both adult and juvenile knock-out mice. With the exception of slightly increased hippocampal SAPAP2 mRNA levels in adult animals, altered postsynaptic protein concentrations do not correlate with similar changes in total and synaptic levels of corresponding mRNAs. Thus, loss of FMRP in neurons appears to mainly affect the translation and not the abundance of particular brain transcripts. Semi-quantitative analysis of RNA levels in FMRP immunoprecipitates showed that in the mouse brain mRNAs encoding PSD components, such as Shank1, SAPAP1-3, PSD-95, and the glutamate receptor subunits NR1 and NR2B, are associated with FMRP. Luciferase reporter assays performed in primary cortical neurons from knock-out and wild-type mice indicate that FMRP silences translation of Shank1 mRNAs via their 3'-untranslated region. Activation of metabotropic glutamate receptors relieves translational suppression. As Shank1 controls dendritic spine morphology, our data suggest that dysregulation of Shank1 synthesis may significantly contribute to the abnormal spine development and function observed in brains of fragile X syndrome patients.
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PMID:Fragile X mental retardation protein regulates the levels of scaffold proteins and glutamate receptors in postsynaptic densities. 1964 Aug 47

Fragile X syndrome (FXS), a common form of inherited mental retardation, is caused by the lack of fragile X mental retardation protein (FMRP). The animal model of FXS, Fmr1 knockout mice, have deficits in the Morris water maze and trace fear memory tests, showing impairment in hippocampus-dependent learning and memory. However, results for synaptic long-term potentiation (LTP), a key cellular model for learning and memory, remain inconclusive in the hippocampus of Fmr1 knockout mice. Here, we demonstrate that FMRP is required for glycine induced LTP (Gly-LTP) in the CA1 of hippocampus. This form of LTP requires activation of post-synaptic NMDA receptors and metabotropic glutamateric receptors, as well as the subsequent activation of extracellular signal-regulated kinase (ERK) 1/2. However, paired-pulse facilitation was not affected by glycine treatment. Genetic deletion of FMRP interrupted the phosphorylation of ERK1/2, suggesting the possible role of FMRP in the regulation of the activity of ERK1/2. Our study provide strong evidences that FMRP participates in Gly-LTP in the hippocampus by regulating the phosphorylation of ERK1/2, and that improper regulation of these signaling pathways may contribute to the learning and memory deficits observed in FXS.
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PMID:Fragile X mental retardation protein is required for chemically-induced long-term potentiation of the hippocampus in adult mice. 1965 72

Fragile X syndrome (FXS), the most common form of inherited mental retardation, is caused by the loss of functional fragile X mental retardation protein (FMRP). FMRP is an RNA-binding protein that can regulate the translation of specific mRNAs. It is known to regulate synaptic development through the regulation of local protein synthesis in synapses. MicroRNAs (miRNAs) are a class of small noncoding RNAs involved in almost every biological process. They exhibit spatiotemporal expression during brain development, and some miRNAs play important roles in neural development. A growing body of evidence now implicates the miRNA pathway in the molecular pathogenesis of FXS. Here we review the current state of knowledge about the microRNA pathway in neural development and the emergence of possible roles for miRNAs in FXS.
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PMID:Macro role(s) of microRNAs in fragile X syndrome? 1966 47

Fragile X syndrome (FXS) is the most common form of inherited mental retardation, characterized by moderate-to-severe mental retardation, attention deficits, and hyperactivity. This disease results from the expansion of a trinucleotide repeat (CGG) within the X-linked fragile X mental retardation 1 (FMR1) gene, which leads to the lack of the product of the FMR1 gene-fragile X mental retardation protein. Many mental disorders such as FXS and Rett syndrome are thought to originate during early developmental period, but recent findings have suggested the involvement of the processes in the adult nervous system. Here we outline our recent studies and initial clinical trials that may provide an approach to treat FXS in the adulthood.
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PMID:Potential pharmacological treatment of fragile X syndrome during adulthood. 1978 85

Fragile X syndrome (FXS) is the most prevalent form of heritable mental retardation. It arises from a mutation in the FMR1 gene on the X chromosome that interferes with expression of fragile X mental retardation protein (FMRP) and leads to a wide range of behavioural and cognitive deficits. Previous studies have shown a deficit in basic visual perceptual processing as well as spatial abilities in FXS. How such a deficit may impact spatial navigation remains unknown. The current study extended previous research by evaluating spatial learning and memory using both virtual and physical versions of Hebb-Williams mazes, which allows for testing of humans and animals under comparable conditions. We compared the performance of individuals affected by FXS to typically developing individuals of equivalent mental age as well as the performance of Fmr1 knockout mice to wild-type control mice on the same maze problems. In human participants, performance of the comparison group improved across trials, showing expected significant decreases in both errors and latency. In contrast, the performance of the fragile X group remained at similar levels across trials. Although wild-type control mice made significantly fewer errors than the Fmr1 knockout mice, latencies were not statistically different between the groups. These findings suggest that affected humans and mice show similar spatial learning deficits attributable to the lack of FMRP. The implications of these data are discussed including the notion that Hebb-Williams mazes may represent a useful tool to examine the impact of pharmacological interventions on mitigating or reversing the symptoms associated with FXS.
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PMID:A comparative study of the performance of individuals with fragile X syndrome and Fmr1 knockout mice on Hebb-Williams mazes. 1979 32

The gene responsible for Fragile X syndrome, fragile X mental retardation-1 (FMR1), contains an unstable sequence of CGG trinucleotide repeats in its promoter region. Expansions of >200 trinucleotide repeats are considered full mutations and typically lead to abnormal methylation of the region resulting in loss of FMR1 expression. Males with loss of FMR1 protein are expected to be affected by Fragile X syndrome while females may or may not clinically manifest features of the condition. The protocols in this unit outline the complementary use of polymerase chain reaction (PCR) and methylation-sensitive Southern blot hybridization to accurately measure trinucleotide repeat size and methylation status. These protocols are also used to evaluate CGG repeat size in two adult-onset conditions known for their association with FMR1 premutation alleles, Fragile X Tremor/Ataxia (FXTAS) syndrome and Premature Ovarian Failure (POF).
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PMID:Molecular analysis of Fragile X syndrome. 1980 93

Fragile X syndrome, the most frequent form of familial mental retardation, is caused by mutation of the Fmr1 gene. Fmr1 encodes the fragile X mental retardation protein (FMRP), an mRNA binding protein regulating local, postsynaptic mRNA translation along dendrites necessary for long-term synaptic plasticity. However, recent studies on FMRP localization in axons and growth cones suggest a possible function in the regulation of local protein synthesis needed for axon guidance. Here, we have demonstrated that FMRP is involved in axonal and growth cone responses induced by the axon guidance factor, Semaphorin-3A (Sema3A). In cultured hippocampal neurons from wild type mice, Sema3A-induced growth cone collapse was protein synthesis-dependent. In contrast, Sema3A-induced growth cone collapse was attenuated in Fmr1 knock-out (KO) neurons and insensitive to protein synthesis inhibitors, suggesting that FMRP is involved in protein synthesis-dependent growth cone collapse. Sema3A increased phosphorylation of eukaryotic initiation factor 4E (eIF4E), an indicator of local translation, in distal axons and growth cones of wild type, but not Fmr1 KO neurons. Furthermore, Sema3A rapidly induced a protein synthesis-dependent increase in levels of microtubule associated protein 1B (MAP1B) in distal axons of wild type neurons, but this response was attenuated in Fmr1 KO neurons. These results suggest a possible role of FMRP to regulate local translation and axonal protein localization in response to Sema3A. This study reveals a new link between FMRP and semaphorin signaling in vitro, and raises the possibility that FMRP may have a critical role in semaphorin signaling in axon guidance during brain development.
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PMID:Fragile X Mental Retardation Protein is Involved in Protein Synthesis-Dependent Collapse of Growth Cones Induced by Semaphorin-3A. 1982 18

The fragile X syndrome (FXS) is the most common form of inherited mental retardation. Caused by a transcriptional silencing of the fragile X mental retardation protein (FMRP), a mRNA binding protein itself, misregulated translation is thought to be the leading cause of the fragile X syndrome. Interestingly, recent results indicated several neuroligin interacting proteins to be affected by this misregulation, including neurexin1 and PSD95, which have also been implicated in autism spectrum disorders. Using co-immunoprecipitation assays and RT-PCR, FMRP is shown to interact with neuroligin1- and 2-mRNA, while no interaction with neuroligin3-mRNA is observed. In line with FMRP's role in translation regulation, Western blot as well as immunohistochemistry analysis reveal changes in protein expression levels suggesting impaired synaptic function. As increasing evidence indicates neuroligin expression to be critical for synapse maturation and function, consequences of impaired neuroligin1 expression in FXS are assessed by overexpressing HA-neuroligin1 in FMR1-/- mice, a model for FXS. Behavioural assessments demonstrate that enhanced neuroligin1 expression improves social behaviour in FMR1-/- mice, whereas no positive effect on learning and memory is seen. These results provide for the first time evidence for an involvement of a neuroligin-neurexin protein network in core symptoms of FXS.
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PMID:Altered neuroligin expression is involved in social deficits in a mouse model of the fragile X syndrome. 1993 34

Fragile X syndrome, the most common form of inherited mental retardation and leading genetic cause of autism, is caused by transcriptional silencing of the Fmr1 gene. The fragile X mental retardation protein (FMRP), the gene product of Fmr1, is an RNA binding protein that negatively regulates translation in neurons. The Fmr1 knock-out mouse, a model of fragile X syndrome, exhibits cognitive deficits and exaggerated metabotropic glutamate receptor (mGluR)-dependent long-term depression at CA1 synapses. However, the molecular mechanisms that link loss of function of FMRP to aberrant synaptic plasticity remain unclear. The mammalian target of rapamycin (mTOR) signaling cascade controls initiation of cap-dependent translation and is under control of mGluRs. Here we show that mTOR phosphorylation and activity are elevated in hippocampus of juvenile Fmr1 knock-out mice by four functional readouts: (1) association of mTOR with regulatory associated protein of mTOR; (2) mTOR kinase activity; (3) phosphorylation of mTOR downstream targets S6 kinase and 4E-binding protein; and (4) formation of eukaryotic initiation factor complex 4F, a critical first step in cap-dependent translation. Consistent with this, mGluR long-term depression at CA1 synapses of FMRP-deficient mice is exaggerated and rapamycin insensitive. We further show that the p110 subunit of the upstream kinase phosphatidylinositol 3-kinase (PI3K) and its upstream activator PI3K enhancer PIKE, predicted targets of FMRP, are upregulated in knock-out mice. Elevated mTOR signaling may provide a functional link between overactivation of group I mGluRs and aberrant synaptic plasticity in the fragile X mouse, mechanisms relevant to impaired cognition in fragile X syndrome.
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PMID:Dysregulation of mTOR signaling in fragile X syndrome. 2050 79

The fragile X syndrome (FXS) is caused by silencing of the fragile X mental retardation gene (FMR1) and the absence of its product, fragile X mental retardation protein (FMRP), resulting from CpG island methylation associated with large CGG repeat expansions (more than 200) termed full mutation (FM). We have identified a number of novel epigenetic markers for FXS using matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS), naming the most informative fragile X-related epigenetic element 1 (FREE1) and 2 (FREE2). Methylation of both regions was correlated with that of the FMR1 CpG island detected using Southern blot (FREE1 R = 0.97; P < 0.00001, n = 23 and FREE2 R = 0.93; P < 0.00001, n = 23) and negatively correlated with lymphocyte expression of FMRP (FREE1 R = -0.62; P = 0.01, n = 15 and FREE2 R = -0.55; P = 0.03, n = 15) in blood of partially methylated 'high functioning' FM males. In blood of FM carrier females, methylation of both markers was inversely correlated with the FMR1 activation ratio (FREE1 R = -0.93; P < 0.0001, n = 12 and FREE2 R = -0.95; P < 0.0001, n = 9). In a sample set of 49 controls, 18 grey zone (GZ 40-54 repeats), 22 premutation (PM 55-170 repeats) and 22 (affected) FXS subjects, the FREE1 methylation pattern was consistent between blood and chorionic villi as a marker of methylated FM alleles and could be used to differentiate FXS males and females from controls, as well as from carriers of GZ/PM alleles, but not between GZ and PM alleles and controls. Considering its high-throughput and specificity for pathogenic FM alleles, low cost and minimal DNA requirements, FREE MALDI-TOF MS offers a unique tool in FXS diagnostics and newborn population screening.
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PMID:Methylation of novel markers of fragile X alleles is inversely correlated with FMRP expression and FMR1 activation ratio. 2011 48


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