Epigenetic application in Fragile x Syndrome
Epigenetic application:
In Fragile X syndrome epigenetics are involved in causing the disease. Epigenetics modifications in fragile x syndrome result in FMR1 silencing.
FMR1 Silencing:
Fragile X Syndrome:
Fragile X syndrome is the most common heritable form of cognitive impairment, it is inherited as an X-linked trait and is caused by a defiency in the fragil X mental retardation protein (FMRP).
Most patients lack of FMRP because of an unestable expansion of a CGG trinucleotide repeat sequence in the 5'- untranslated region of FMR1 gene.
Individuals carry 5 to 55 repeat copies, while affected patients carry over 200 copies(full mutation).
Consequences:
As a consequence, gene transcription is inhibited leading to the absense of its protein product FMRP. Some alleles remain partially or even fully unmethylated cause differences in methylation status are poorly understood despite containing 200 CGG repeats.
The expansion of the CGG trinucleotide repeat sequence in the 5' untranslated region of the FMR1 gene (Avitzour.,Mor-shaked,2014), it is attributed to epigenetic regulated transcirptional silencing,although this expansion can cause translation supression of FMRP protein of FMR1 gene(Warren,S,2007).That expansion can cause FMR1 gene to turn off(Alzforum networking for a cure,2014). Full expansion of the CGG repeat coincides with hypermethylation of the repeat region and its regulatory site CpG Island. Near the FMR1 there a regulatory site called CpG island, this site is methylated, as a result the cell is unable to copy the information in the FMR1 gene. Since mRNA copy is not made, FMRP will no te be synthesized, since there is no FMRP protein the characteristics of fragile x syndrome begin to show. DNA hypermethylation v vb This epigenetic changes, local aquirement of abnormal DNA hypermethylation and the gain of repressive histone modifications are related with nuclease sensitivity differences and seem to be critical from the transition from active to inactive chromatin configuration.
Epigenetic modulators:
Strategy of restoring FMR1 gene activity is based on the presence of the intact FMR1 coding sequence, targets potencially reversible epigenetic changes. (Bagni.,Hagerman.,Neri.,Tassone,2012)
1st compound tested:
Drug 5' aza-deoxycytidine a methyltransferase inhibitor,which restored transcription and translation of the FMR1 gene. Treatment with deacetylase inhibitors potentiated the effect of 5' azadC. Reactivation was accompained by DNA methylation but also by changes in the epigenetic code of histones H3 and H4. As a result of these changes, the inactive methylated FM allele became similar to the active UFM allele. The cause of this reduction in methylations unknown, converting a carrier of a methylated FM allele into a carrier of an UFM allele.(Bagni.,Hagerman.,Neri.,Tassone,2012)