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The Fragile X Syndrome – Where Do We Go?

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Affecting about 1 in 4000 males and 7000 females, the Fragile X Syndrome (FXS) represents the most common form of inherited mental retardation in all human populations and ethnic groups. Impaired individuals display a variety of intellectual deficits ranging from mild learning handicaps to severe cognitive ...

Affecting about 1 in 4000 males and 7000 females, the Fragile X Syndrome (FXS) represents the most common form of inherited mental retardation in all human populations and ethnic groups. Impaired individuals display a variety of intellectual deficits ranging from mild learning handicaps to severe cognitive disabilities with IQs as low as 40-50, but also autistic behaviours as well as epileptic seizures characterize the disease.

The complaints are caused by the loss of a single protein, the Fragile X Mental Retardation Protein FMRP, which functions to regulate the mRNA metabolism in various aspects. Studies demonstrated that FMRP is able to associate with a diversity of mRNAs -approximately 4% of all mRNAs in the mammalian brain- by interacting with several different RNA-motifs. Thereby, FMRP regulates not only mRNA transport and stability of its partner mRNAs, but also mRNA translation. Since G-quartets present in the mRNA of FMRP were found to function as exonic splicing enhancers, FMRP was also suggested to take action in alternative splicing.

On the other hand, FMRP itself turned out to be under control of signalling cascades of group 1 metabotropic glutamate receptors (gp1 mGluRs; mGluR1&5), hence allowing for an activity dependent regulation of the mRNA metabolism in various aspects by FMRP. Subsequent studies gave rise to the mGluRTheory of FXS: The theory states that FMRP normally acts as a repressor of mRNA translation downstream of gp1 mGluRs, which is released after mGluR activation and thereby induces the translation of proteins required for the expression of LTD. Hence, in the absence of FMRP, persistent and mGluR stimulation independent synthesis of LTD-proteins causes ongoing AMPAR internalization.

Indeed, there is good evidence for this theory. The use of the mGluR5 antagonist MPEP has been shown to improve many symptoms of FXS in FMR1-/- mice, a model of the disease. These promising results have prompted clinical trials with mGluR antagonists to downregulate mGluR signalling, but although patients treated with these substances were initially reported to experience some behavioural improvements, all trials were discontinued during phases IIb/III since the studies did not show any significant improvements in abnormal behaviours compared to placebo.

Since then, research has been continuing, and in line with the complexity of the disease, various directions are being explored including Metalloproteinase function, GABAa signalling, the role of glia cells, mechanisms of neurogenesis and neurodevelopment and many more. However, the contributions of most of these mechanisms to the specific symptoms of FXS have often remained elusive, and the translations of findings from mouse to men challenging.

We would like to bring together new findings, ideas, comments, thoughts and perspectives from all kind of different research areas of the field to stimulate discussions and improve our understanding of this exceptional disease. We welcome studies using humans, animal models or basic research techniques and encourage submissions of all article types such as Original Research (positive and/or negative results), Methods, Hypothesis & Theory, Clinical studies, Reviews and Comments. Short Communications providing a comprehensive analysis of any topic of interest are very welcome.


Keywords: Fragile X Syndrome, FXS, inherited mental retardation, FMRP, Autism Spectrum Disorder


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