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Annu Rev Pathol. 2012;7:219-45. doi: 10.1146/annurev-pathol-011811-132457. Epub 2011 Oct 10.

Molecular mechanisms of fragile X syndrome: a twenty-year perspective.

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  • 1Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322, USA.


Fragile X syndrome (FXS) is a common form of inherited intellectual disability and is one of the leading known causes of autism. The mutation responsible for FXS is a large expansion of the trinucleotide CGG repeat in the 5' untranslated region of the X-linked gene FMR1. This expansion leads to DNA methylation of FMR1 and to transcriptional silencing, which results in the absence of the gene product, FMRP, a selective messenger RNA (mRNA)-binding protein that regulates the translation of a subset of dendritic mRNAs. FMRP is critical for mGluR (metabotropic glutamate receptor)-dependent long-term depression, as well as for other forms of synaptic plasticity; its absence causes excessive and persistent protein synthesis in postsynaptic dendrites and dysregulated synaptic function. Studies continue to refine our understanding of FMRP's role in synaptic plasticity and to uncover new functions of this protein, which have illuminated therapeutic approaches for FXS.

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