By creating neurons from induced pluripotent stem (iPS) cells generated from somatic cells taken from Fragile X patients, researchers have created a cell type relevant for both disease modeling and drug screening.

Fragile X (FX) syndrome belongs to the autism spectrum disorders, and is the most common cause of inherited mental retardation in boys. It is nearly always caused by silencing of the FMR1 (Fragile X mental retardation 1) gene due to abnormal CGG repeat expansions in the five prime untranslated region (5′-UTR) of the gene. This area of the gene does not code for proteins but does contain regulatory elements. Abnormal CGG repeat expansion of over 200 repeats leads to silencing of the gene due to methylation of the gene 5′-UTR and the gene promoter elements.

Investigators at the Hebrew University of Jerusalem (Israel) had already generated 11induced pluripotent stem cell lines (FX-iPS) from the skin cells of three different FX patients. In the current study, published in the March 19, 2012, online edition of the Journal of Molecular Cell Biology, they exploited these cell lines to generate Fragile X neuronal cells.

Fragile X neuronal cells were then used for screening of several chromatin remodeling drugs in the hope that some might be able to repair the damaged FMR1 gene and restore its normal expression and protein synthetic activity.

Results revealed that the histone deacetylase inhibitor trichostatin-A (TSA) had no significant effect on FMR1 reactivation. On the other hand, the demethylating agent 5-azacytidine (5-azaC) was able to robustly reactivate FMR1 gene expression in the FX-iPS cells.

The compound 5-azaC is an already established drug known to function by removing methyl groups from regulatory elements of genes. However, this is the first time that it has been shown to demethylate successfully a gene in neurons or stem cells of Fragile X patients.

“There is still a substantial gap between the restoration of gene expression in cultured patients’ cells and restoring it in patients; however, the finding that it is possible to restore gene expression in neuronal cells paves the way for further study of its restoration in patients,” said first author Ori Bar-Nur, doctoral researcher at the Hebrew University of Jerusalem. “New technologies developed in recent years in the stem cell field allow us to conduct research that was not possible until recently.”

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