Fragile X syndrome: Causes, diagnosis, mechanisms, and therapeutics

The Journal of clinical investigation (Impact Factor: 13.22). 12/2012; 122(12):4314-22. DOI: 10.1172/JCI63141
Source: PubMed


Fragile X syndrome (FXS) is the most frequent form of inherited intellectual disability and is also linked to other neurologic and psychiatric disorders. FXS is caused by a triplet expansion that inhibits expression of the FMR1 gene; the gene product, FMRP, regulates mRNA metabolism in the brain and thus controls the expression of key molecules involved in receptor signaling and spine morphology. While there is no definitive cure for FXS, the understanding of FMRP function has paved the way for rational treatment designs that could potentially reverse many of the neurobiological changes observed in FXS. Additionally, behavioral, pharmacological, and cognitive interventions can raise the quality of life for both patients and their families.

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    • "It is thought that this is achieved through binding of the mRNA by the FMR protein [23] [25]. While the brain and the nervous system have been the focus of studies on FMR function [21] [23] [25], recent studies have begun to add to the knowledge of FMRs role in other contexts. For example, it was recently demonstrated that the FMR1 gene is up-regulated in cancer cells like the hepatocellular carcinoma where it aids in tumor migration and metastasis [26]. "
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    ABSTRACT: Malignant pleural mesothelioma (MPM) is an aggressive form of thoracic cancer with poor prognosis. While some studies have identified the molecular alterations associated with MPM, little is known about their role in MPM. For example, fragile X mental retardation (FMR) gene is up-regulated in MPM but its role in MPM is unknown. Here, utilizing Drosophila genetics, I investigate the possible role FMR may be playing in MPM. I provide evidence which suggests that FMR may contribute to tumorigenesis by up-regulating a matrix metalloprotease (MMP) and by degrading the basement membrane (BM), both important for tumor metastasis. I also demonstrate a novel link between FMR and the JNK pathway and suggest that the effects of FMR in MPM could in part be mediated by up-regulation of the JNK pathway.
    FEBS Open Bio 10/2015; 5:705-11. DOI:10.1016/j.fob.2015.07.005 · 1.52 Impact Factor
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    • "fmr1 [fragile X mental retardation 1] knockout mice, Black and Tan BRachyury (BTBR) mice, and valproic acid-treated rats), that display autistic-like features. Fragile X syndrome (FXS) is an inherited disorder caused by mutations in the fmr1 gene, that is translated into the fragile X mental retardation 1 protein (FMRP), that in turn plays a role in the development of synapses [97] [98]. Expansion mutations of the fmr1 gene produce autistic features in approximately 40% of FXS patients, and thus FXS provides a valuable model for identifying novel biomarkers/targets for autism and for dissecting the underlying neurochemical pathways [99]. "
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    ABSTRACT: Autism spectrum disorder (ASD) is a complex behavioral condition with onset during early childhood and a lifelong course in the vast majority of cases. To date, no behavioral, genetic, brain imaging, or electrophysiological test can specifically validate a clinical diagnosis of ASD. However, these medical procedures are often implemented in order to screen for syndromic forms of the disorder (i.e., autism comorbid with known medical conditions). In the last 25 years a good deal of information has been accumulated on the main components of the "endocannabinoid (eCB) system", a rather complex ensemble of lipid signals ("endocannabinoids"), their target receptors, purported transporters, and metabolic enzymes. It has been clearly documented that eCB signaling plays a key role in many human health and disease conditions of the central nervous system, thus opening the avenue to the therapeutic exploitation of eCB-oriented drugs for the treatment of psychiatric, neurodegenerative, and neuroinflammatory disorders. Here we present a modern view of the eCB system, and alterations of its main components in human patients and animal models relevant to ASD. This review will thus provide a critical perspective necessary to explore the potential exploitation of distinct elements of eCB system as targets of innovative therapeutics against ASD.
    Journal of the American Society for Experimental NeuroTherapeutics 07/2015; DOI:10.1007/s13311-015-0371-9 · 5.05 Impact Factor
    • "repressor and thereby regulates activity-dependent translation of a number of mRNAs (Brown et al., 2001; Akins et al., 2009, 2012; Strumbos et al., 2010; Zhang et al., 2012). Additionally, FMRP is believed to selectively bind approximately 4% of all mRNAs in the mammalian brain, many of which are known to code for proteins involved in neuronal maturation and synaptic plasticity (Brown et al., 2001; Till, 2010; Bagni et al., 2012). The absence of FMRP (in humans and Fmr1 KO animals) results in dysregulated translation of select mRNAs, abnormal synaptic function, dendritic dysmorphology characteristic of immature neurons, and a loss of protein synthesis-dependent plasticity leading to disordered expression of normally regulated proteins (Rudelli et al., 1985; Hinton et al., 1991; Comery et al., 1997; Irwin et al., 2000; Nimchinsky et al., 2001; Galvez et al., 2003; Pfeiffer and Huber, 2009; Zhang et al., 2009; Strumbos et al., 2010; Deng et al., 2011). "
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    ABSTRACT: Fragile X syndrome (FXS) is an inherited neurodevelopmental disorder affecting nearly 1 in 5,000 newborn males and is a leading genetic cause of autism spectrum disorder. In addition to developmental delays and intellectual impairment, FXS is characterized by seizures, attention deficit, and hypersensitivity to visual, tactile and auditory stimuli. The Fmr1 gene encodes Fragile X mental retardation protein (FMRP), which is abundant in neurons, binds select mRNAs and functions as a negative regulator of mRNA translation. A deficiency in FMRP, as in FXS and Fmr1 knockout animals, results in neuronal dysmorphology and altered synaptic function. Additionally, there is evidence for disruption of GABAergic circuits in subjects lacking FMRP. Our previous studies demonstrated widespread expression of FMRP in human auditory brainstem neurons. Given this observation, we hypothesized that FMRP is highly expressed in rat auditory brainstem neurons and that the auditory hypersensitivity characteristic of FXS results from dysfunction of brainstem networks secondary to decreased expression of FMRP. In our investigation of postnatal day 50 (P50) control rats, we found that FMRP was widely expressed in neurons of the superior olivary complex (SOC). In P50 Fmr1 knockout rats, many SOC neurons had a smaller soma when compared to controls, indicative of abnormal neuronal morphology. Additionally, neurons in the medial superior olive (MSO) were more round in Fmr1 knockout rats. There was also reduced expression of glutamic acid decarboxylase (GAD67) in neurons of the superior paraolivary nucleus (SPON) and a reduction in the number of calretinin-immunoreactive terminals associated with neurons of the medial nucleus of the trapezoid body (MNTB). Together, these findings support the conclusion that the auditory dysfunction characteristic of FXS arises, at least in part, from defective brainstem networks. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.
    Neuroscience 07/2015; 303. DOI:10.1016/j.neuroscience.2015.06.061 · 3.36 Impact Factor
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