Fragile X syndrome: From molecular genetics to therapy

Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
Journal of Medical Genetics (Impact Factor: 6.34). 10/2009; 46(9):577-84. DOI: 10.1136/jmg.2008.064667
Source: PubMed


Fragile X syndrome, the main cause of inherited mental retardation, is caused by transcriptional silencing of the fragile X mental retardation gene, FMR1. Absence of the associated protein FMRP leads to the dysregulation of many genes creating a phenotype of ADHD, anxiety, epilepsy and autism. The core aim of this review is to summarise two decades of molecular research leading to the characterisation of cellular and molecular pathways involved in the pathology of this disease and as a consequence to the identification of two new promising targets for rational therapy of fragile X syndrome, namely the group 1 metabotrope glutamate receptors (Gp1 mGluRs) and the gamma-amino butyric acid A receptors (GABA(A)Rs). As no current clinical treatments are directed specifically at the underlying neuronal defect due to absence of FMRP, this might open new powerful therapeutic strategies.

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Available from: Charlotte D'Hulst, Mar 11, 2015
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    • "FRDA is one of several diseases caused by triplet repeats located in non-coding regions. One important example of these tri-nucleotide repeat diseases is the neuropsychiatric disorder Fragile X syndrome, where a CGG@BULLETCCG tract resides within the 5′ UTR of the Fragile X mental retardation 1 (FMR1) gene (Pieretti et al. 1991; D'Hulst and Kooy 2009). DNA methylation, heterochromatic histone marks (e.g. "
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    • "Extensive functional analysis of these neurons shows that FMR1 down-regulation leads to the formation of neurons with poor synaptic capability and lack of response to glutamate. FMR1 expression was already shown to be restricted mainly to the central nervous system during human embryogenesis (Abitbol et al., 1993), and its absence was shown to be coupled with abnormal neurogenesis (Castren, 2006; D'Hulst and Kooy, 2009). However, the spatiotemporal sequence of events linking between gradual down-regulation of FMR1 and abnormal neurogenesis are difficult to observe in KO animal models, since FMR1 expression is absent in these animals even at early stages of development. "
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    • "Current knowledge surrounding the pathophysiology of FXS has been greatly advanced by the development of animal models [95]. These transgenic animals do not carry the trinucleotide expansion but do have functional deletions of FMRP. "
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