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, the most frequent form of inherited mental retardation, is due to the absence of Fragile X Mental Retardation Protein (FMRP), an RNA-binding protein involved in several steps of RNA metabolism. To date, two RNA motifs have been found to mediate FMRP/RNA interaction, the G-quartet and the "kissing complex," which both induce translational repression in the presence of FMRP. We show here a new role for FMRP as a positive modulator of translation. FMRP specifically binds Superoxide Dismutase 1 (Sod1) mRNA with high affinity through a novel RNA motif, SoSLIP (Sod1 mRNA Stem Loops Interacting with FMRP), which is folded as three independent stem-loop structures. FMRP induces a structural modification of the SoSLIP motif upon its interaction with it. SoSLIP also behaves as a translational activator whose action is potentiated by the interaction with FMRP. The absence of FMRP results in decreased expression of Sod1. Because it has been observed that brain metabolism of FMR1 null mice is more sensitive to oxidative stress, we propose that the deregulation of Sod1 expression may be at the basis of several traits of the physiopathology of the Fragile X syndrome, such as anxiety, sleep troubles, and autism.
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PMID:A novel function for fragile X mental retardation protein in translational activation. 1916 69

Fragile X syndrome afflicts 1 in 2,500 individuals and is the leading heritable cause of mental retardation worldwide. The overriding clinical manifestation of this disease is mild to severe cognitive impairment. Age-dependent cognitive decline has been identified in Fragile X patients, although it has not been fully characterized nor examined in animal models. A Drosophila model of this disease has been shown to display phenotypes bearing similarity to Fragile X symptoms. Most notably, we previously identified naive courtship and memory deficits in young adults with this model that appear to be due to enhanced metabotropic glutamate receptor (mGluR) signaling. Herein we have examined age-related cognitive decline in the Drosophila Fragile X model and found an age-dependent loss of learning during training. We demonstrate that treatment with mGluR antagonists or lithium can prevent this age-dependent cognitive impairment. We also show that treatment with mGluR antagonists or lithium during development alone displays differential efficacy in its ability to rescue naive courtship, learning during training and memory in aged flies. Furthermore, we show that continuous treatment during aging effectively rescues all of these phenotypes. These results indicate that the Drosophila model recapitulates the age-dependent cognitive decline observed in humans. This places Fragile X in a category with several other diseases that result in age-dependent cognitive decline. This demonstrates a role for the Drosophila Fragile X Mental Retardation Protein (dFMR1) in neuronal physiology with regard to cognition during the aging process. Our results indicate that misregulation of mGluR activity may be causative of this age onset decline and strengthens the possibility that mGluR antagonists and lithium may be potential pharmacologic compounds for counteracting several Fragile X symptoms.
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PMID:Age-dependent cognitive impairment in a Drosophila fragile X model and its pharmacological rescue. 2003 5

Fragile X Syndrome (FXS) is the most common single gene cause of inherited mental impairment, and cognitive deficits can range from simple learning disabilities to mental retardation. Human FXS is caused by a loss of the Fragile X Mental Retardation Protein (FMRP). The fragile X knockout (FX KO) mouse also shows a loss of FMRP, as well as many of the physical and behavioural characteristics of human FXS. This work aims to characterize the anatomical changes between the FX KO and a corresponding wild type mouse. Significant volume decreases were found in two regions within the deep cerebellar nuclei, namely the nucleus interpositus and the fastigial nucleus, which may be caused by a loss of neurons as indicated by histological analysis. Well-known links between these nuclei and previously established behavioural and physical characteristics of FXS are discussed. The loss of FMRP has a significant effect on these two nuclei, and future studies of FXS should evaluate the biochemical, physiological, and behavioral consequences of alterations in these key nuclei.
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PMID:Anatomical phenotyping in a mouse model of fragile X syndrome with magnetic resonance imaging. 2030 74

Fragile X syndrome (FXS), the most common genetic form of mental retardation and autism, is caused by loss-of-function mutations in an RNA-binding protein, Fragile X Mental Retardation Protein (FMRP). Neurons from patients and the mouse Fmr1 knockout (KO) model are characterized by an excess of dendritic spines, suggesting a deficit in excitatory synapse elimination. In response to neuronal activity, myocyte enhancer factor 2 (MEF2) transcription factors induce robust synapse elimination. Here, we demonstrate that MEF2 activation fails to eliminate functional or structural excitatory synapses in hippocampal neurons from Fmr1 KO mice. Similarly, inhibition of endogenous MEF2 increases synapse number in wild-type but not Fmr1 KO neurons. MEF2-dependent synapse elimination is rescued in Fmr1 KO neurons by acute postsynaptic expression of wild-type but not RNA-binding mutants of FMRP. Our results reveal that active MEF2 and FMRP function together in an acute, cell-autonomous mechanism to eliminate excitatory synapses.
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PMID:Fragile X mental retardation protein is required for synapse elimination by the activity-dependent transcription factor MEF2. 2043 96

Regulation of post-transcriptional gene expression is a cellular process that is accomplished through the activity of multiple mRNP (messenger RiboNucleoProtein) complexes which are composed of mRNA-binding proteins and RNA molecules interacting with those proteins. The specificity of these interactions is mediated by the ability of the RNA-binding proteins to precisely recognize and bind RNA sequences or structures. Alterations of their function may have some dramatic consequences, resulting in different pathologies. An increasing body of data is emerging showing the impact of a G-quadruplex forming structure in the maturation and expression of some RNA molecules. We review here the role of the G-quadruplex RNA structure in the regulation of translation and splicing, when it interacts with two RNA-binding proteins: FMRP (Fragile X Mental Retardation Protein) and FMR2P (Fragile X Mental Retardation 2 protein). Impaired expression of these proteins causes two forms of intellectual disability: the Fragile X Mental Retardation syndrome (FXS) and the FRAXE-associated mental retardation (FRAXE), respectively. FMRP is involved in different steps of RNA metabolism and, in particular, in translational regulation. FMR2P has been initially described as a transcription factor and we recently showed also its role in regulation of alternative splicing. By the study of the functional significance of the interaction of both FMRP and FMR2P with a G-quadruplex forming RNA we were able to show an impact of this structure in translational regulation and also in splicing, behaving as an Exonic Splicing Enhancer.
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PMID:The role of G-quadruplex in RNA metabolism: involvement of FMRP and FMR2P. 2057 Jul 7

Fragile X Syndrome (FXS) is the most common form of inherited mental retardation in men. It is caused by abnormalities in the FMR1 gene that are associated with CGG repeat expansion and the hypermethylation status of its promoter. Methylated alleles lead to transcriptional inhibition and consequent loss of Fragile X Mental Retardation Protein. Chemical modification of cytosine to uracil by bisulfite treatment has proved to be an attractive method for DNA methylation studies that precludes labor-intensive Southern blot analysis, which is the gold standard test for FXS. In this report, bisulfite-treated DNA samples were amplified using real-time multiplex methylation-specific polymerase chain reaction followed by melting curve analysis. Our results show that all control samples with known CGG repeat numbers and methylation statuses were correctly diagnosed. The samples from 43 male patients were also successfully diagnosed, which were in complete agreement with the results of Southern blotting. By such means, 39 patients were found to have an unmethylated allele; 3, a fully mutated allele; and 1, both methylated and unmethylated alleles, thus implying a diagnosis of mosaicism. In conclusion, we find our method to be convenient for screening a large number of male patients with FXS, because it is rapid and easy to perform, especially when there is a low quantity of DNA that must be sensitively and accurately assayed.
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PMID:A new method for FMR1 gene methylation screening by multiplex methylation-specific real-time polymerase chain reaction. 2132 65

Fragile X syndrome (FXS) is the most common form of inherited mental retardation and is caused by the loss of function for Fragile X Mental Retardation Protein (FMRP), a selective RNA-binding protein with a demonstrated role in the localized translation of target mRNAs at synapses. Several recent studies provide compelling evidence for a new role of FMRP in the development of the nervous system, during neurogenesis. Using a multi-faceted approach and a variety of model systems ranging from cultured neurospheres and progenitor cells to in vivo Drosophila and mouse models these reports indicate that FMRP is required for neural stem and progenitor cell proliferation, differentiation, survival, as well as regulation of gene expression. Here we compare and contrast these recent reports and discuss the implications of FMRP's new role in embryonic and adult neurogenesis, including the development of novel therapeutic approaches to FXS and related neurological disorders such as autism.
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PMID:Heads-up: new roles for the fragile X mental retardation protein in neural stem and progenitor cells. 2140 21

The Fragile X syndrome (FXS) is the most frequent form of inherited mental retardation and also considered a monogenic cause of Autism Spectrum Disorder. FXS symptoms include neurodevelopmental delay, anxiety, hyperactivity, and autistic-like behavior. The disease is due to mutations or loss of the Fragile X Mental Retardation Protein (FMRP), an RNA-binding protein abundant in the brain and gonads, the two organs mainly affected in FXS patients. FMRP has multiple functions in RNA metabolism, including mRNA decay, dendritic targeting of mRNAs, and protein synthesis. In neurons lacking FMRP, a wide array of mRNAs encoding proteins involved in synaptic structure and function are altered. As a result of this complex dysregulation, in the absence of FMRP, spine morphology and functioning is impaired. Consistently, model organisms for the study of the syndrome recapitulate the phenotype observed in FXS patients, such as dendritic spine anomalies and defects in learning. Here, we review the fundamentals of genetic and clinical aspects of FXS, devoting a specific attention to ASD comorbidity and FXS-related diseases. We also review the current knowledge on FMRP functions through structural, molecular, and cellular findings. Finally, we discuss the neuroanatomical, electrophysiological, and behavioral defects caused by FMRP loss, as well as the current treatments able to partially revert some of the FXS abnormalities.
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PMID:Molecular and cellular aspects of mental retardation in the Fragile X syndrome: from gene mutation/s to spine dysmorphogenesis. 2235 Oct 71

The primary transcript of the mammalian Fragile X Mental Retardation-1 gene (Fmr1), like many transcripts in the central nervous system, is alternatively spliced to yield mRNAs encoding multiple proteins, which can possess quite different biochemical properties. Despite the fact that the relative levels of the 12 Fmr1 transcript isoforms examined here vary by as much as two orders of magnitude amongst themselves in both adult and embryonic mouse brain, all are associated with polyribosomes, consistent with translation into the corresponding isoforms of the protein product, FMRP (Fragile X Mental Retardation Protein). Employing the RiboTag methodology developed in our laboratory, the relative proportions of the 7 most abundant transcript isoforms were measured specifically in neurons and found to be similar to those identified in whole brain. Measurements of isoform profiles across 11 regions of adult brain yielded similar distributions, with the exceptions of the hippocampus and the olfactory bulb. These two regions differ from most of the brain in relative amounts of transcripts encoding an alternate form of one of the KH RNA binding domains. A possible relationship between patterns of expression in the hippocampus and olfactory bulb and the presence of neuroblasts in these two regions is suggested by the isoform patterns in early embryonic brain and in cultured neural progenitor cells. These results demonstrate that the relative levels of the Fmr1 isoforms are modulated according to developmental stage, highlighting the complex ramifications of losing all the protein isoforms in individuals with Fragile X Syndrome. It should also be noted that, of the eight most prominent FMRP isoforms (1-3, 6-9 and 12) in mouse, only two have the major site of phosphorylation at Ser-499, which is thought to be involved in some of the regulatory interactions of this protein.
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PMID:FMR1 transcript isoforms: association with polyribosomes; regional and developmental expression in mouse brain. 2350 81

Fragile X syndrome (FXS), a severe neurodevelopmental anomaly, and one of the earliest disorders linked to an unstable ('dynamic') mutation, is caused by the large (>200) CGG repeat expansions in the noncoding portion of the FMR1 (Fragile X Mental Retardation-1) gene. These expansions, termed full mutations, normally silence this gene's promoter through methylation, leading to a gross deficit of the Fragile X Mental Retardation Protein (FMRP) that is essential for normal brain development. Rare individuals with the expansion but with an unmethylated promoter (and thus, FMRP production), present a much less severe form of FXS. However, a unique feature of the relationship between the different sizes of CGG expanded tract and phenotypic changes is that smaller expansions (<200) generate a series of different clinical manifestations and/or neuropsychological changes. The major part of this chapter is devoted to those FMR1 alleles with small (55-200) CGG expansions, termed 'premutations', which have the potential for generating the full mutation alleles on mother-offspring transmission, on the one hand, and are associated with some phenotypic changes, on the other. Thus, the role of several factors known to determine the rate of CGG expansion in the premutation alleles is discussed first. Then, an account ofvarious neurodevelopmental, cognitive, behavioural and physical changes reported in carriers of these small expansions is given, and possible association of these conditions with a toxicity of the elevated FMR1 gene's transcript (mRNA) is discussed. The next two sections are devoted to major and well defined clinical conditions associatedwith the premutation alleles. The first one is the late onsetneurodegenerative disorder termed fragile X-associated tremor ataxia syndrome (FXTAS). The wide range of clinical and neuropsychological manifestations of this syndrome, and their relevance to elevated levels of the FMR1 mRNA, are described. Another distinct disorder linked to the CGG repeat expansions within the premutation range is fragile X-associated primary ovarian insufficiency (FXPOI) in females, and an account of the spectrum of manifestations of this disorder, together with the latest findings suggesting an early onset of the ovarian changes, is given. In the following section, the most recent findings concerning the possible contribution of FMR1 'grey zone' alleles (those with the smallest repeat expansions overlapping withthenormal rangei.e.,41-54CGGs), tothepsychologicalandclinical manifestations, already associated with premutation alleles, are discussed. Special emphasis has been placed on the possibility that the modest elevation of 'toxic' FMR1 mRNA in the carriers of grey zone alleles may present an additional risk for some neurodegenerative diseases, such as those associated with parkinsonism, by synergizing with either other susceptibility genes or environmental poisons. The present status ofthe treatment of fragile X-related disorders, especially FXS, is presented in the last section of this chapter. Pharmacological interventions in this syndrome have recently extended beyond stimulants and antipsychotic medications, and the latest trials involving a group of GluR5 antagonists aim to ascertain if these substances have the potential to reverse some of the neurobiological abnormalities of FXS.
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PMID:Unstable mutations in the FMR1 gene and the phenotypes. 2356 Mar 6


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