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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    • "Fragile X syndrome (FXS) is a rare genetic disorder, mostly characterized by moderate to severe mental retardation, autistic and hyperactive behaviour, macroorchidism, large ears, a prominent jaw, and high-pitched jocular speech [1]. Neuropathological features of the fragile X syndrome are long, thin, and sinuous dendritic spines, increased intracranial volume, enlarged ventricles, increased volumes of selective subcortical grey matter regions, decreased size of "
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    ABSTRACT: Fragile X syndrome is the most common genetic cause of mental disability. Although many research has been performed, the mechanism underlying the pathogenesis is unclear and needs further investigation. Oxidative stress played major roles in the syndrome. The aim was to investigate the nitric oxide metabolism, protein nitration level, the expression of NOS isoforms, and furthermore the activation of the nuclear factor NF- κ B-p65 subunit in different brain areas on the fragile X mouse model. Methods. This study involved adult male Fmr1-knockout and wild-type mice as controls. We detected nitric oxide metabolism and the activation of the nuclear factor NF- κ Bp65 subunit, comparing the mRNA expression and protein content of the three NOS isoforms in different brain areas. Results. Fmr1-KO mice showed an abnormal nitric oxide metabolism and increased levels of protein tyrosine nitrosylation. Besides that, nuclear factor NF- κ B-p65 and inducible nitric oxide synthase appeared significantly increased in the Fmr1-knockout mice. mRNA and protein levels of the neuronal nitric oxide synthase appeared significantly decreased in the knockout mice. However, the epithelial nitric oxide synthase isoform displayed no significant changes. Conclusions. These data suggest the potential involvement of an abnormal nitric oxide metabolism in the pathogenesis of the fragile X syndrome.
    Full-text · Article · Jan 2016 · Oxidative medicine and cellular longevity
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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.
    Full-text · Article · Oct 2015 · FEBS Open Bio
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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.
    Full-text · Article · Jul 2015 · Journal of the American Society for Experimental NeuroTherapeutics
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