Neuropsychiatric Disorders and Epigenetics (Second Edition) - Chapter 6: Epigenetic causes of intellectual disability—the fragile X syndrome paradigm

Fragile X syndrome (FXS), the leading cause of inherited intellectual disability, is a paradigm of epigenetic dysregulation, inducing gene silencing. FXS is caused by so-called “full mutation” of the FMR1 gene, consisting of a CGG triplet expansion over 200 repeats in the 5′ UTR of the gene and subsequent epigenetic modifications resulting in block of transcription and absence of the protein product FMRP. Cytosine methylation is key to the silencing of the gene, as proven by the demonstration that FMR1 activity can be restored in vitro by treating FXS cells with the demethylating agent 5-aza-2-deoxycytidine. This concept is strengthened by the existence of rare carriers of a full mutation, who are unable to methylate the expanded CGGs and are capable of transcribing and translating FMR1 and therefore rescue them from manifesting FXS. Detailed knowledge of this exceptional condition could open the way to an FXS treatment based on reactivation of the mutant gene through removal of the epigenetic block.