Background: Fragile X mental retardation syndrome (FXS) is the most common heritable 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, but may show parallels to Friedreich ataxia, a related disorder that also shows repeat-mediated gene silencing. Progress report: We have previously identified a number of steps in the Fragile X gene silencing process including some that precede DNA methylation and some that occur very late in the silencing process (Biacsi, Kumari and Usdin, 2008). One of the late steps in FX gene silencing turns out to be the deacetylation of histone H4 on lysine 16, a step we showed to be carried out by SIRT1, a class III histone deacetylase. We have shown that SIRT1 inhibition reactivates the FMR1 gene without requiring DNA demethylation (Biacsi, Kumari and Usdin, 2008). It may thus be useful in cells like neurons where the effect of gene silencing is most apparent. We are interested in identifying other compounds capable of ameliorating gene silencing in FXS. To this end we have generated a number of patient-derived Induced Pluripotent Stem Cells. We have differentiated these cells into different medically relevant cell types and used these cells to carry out a variety of screens for compounds capable of alleviating gene silencing in different cell types in collaboration with Drs Zheng and Swaroop at the NIH Chemical Genomics Center. To facilitate this process we have developed an FMRP assay suitable for use in high throughput screens. To date we have identified a number of compounds that may have some therapeutic potential. A more extensive search for other compounds is currently underway.
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