Background: Fragile X mental retardation syndrome (FXS) is the most common familial cause of intellectual disability and the most common known cause of autism. Other symptoms of FXS include depression, sensory processing deficits, aggressive behavior, connective tissue problems and digestive difficulties. This disorder arises when the number of CGG-repeats in the 5 UTR of the FMR1 gene exceeds 200. Such alleles become silenced. This results in a deficiency of the protein product of this gene, FMRP, which is involved in the regulation of translation of a subset of mRNAs. The FMRP deficiency in brain results in aberrant dendritic spine morphology and a defective response to synaptic activation. The mechanism of gene silencing is unknown. Progress report: We have taken 2 broad approaches. One has been to understand the factors important for normal FMR1 expression (Kumari and Usdin, 2001, 2005) and for the expression of an autosomal homolog of FMR1, FXR2, which encodes a protein whose function is thought to partially overlap with FMRP (Mahishi and Usdin, 2006). The second approach has been to study the molecular events involved in the silencing of FXS alleles to try and identify steps that may be amenable to pharmacological intervention. This approach has lead to the demonstration that deacetylation of Histone H4K16 is a late downstream consequence of DNA methylation (Biacsi, Kumari and Usdin, 2008). This deacetylation is carried out by SIRT1, a protein deacetylase belonging to the Sirtuin family. Inhibition of SIRT1 does not require DNA demethylation and thus may be effective in neurons that no longer divide. We have since identified a number of other compounds that are able to either reactivate silenced alleles themselves, or maintain the gene in an active state after reactivation by another compound. Work is underway to try and identify the mechanisms responsible.
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