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The mGluR5 antagonist AFQ056 does not affect methylation and transcription of the mutant FMR1 gene in vitro

DOI: 10.1186/1471-2350-13-13

Keywords: Fragile X syndrome, AFQ056, mGluR5 inhibitors, DNA methylation, Epigenetic modification

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Abstract:

To determine whether AFQ056 may have secondary effects on the methylation and transcription of FMR1, here we treated three FXS lymphoblastoid cell lines and one normal control male line. A quantitative RT-PCR was performed to assess transcriptional reactivation of the FMR1 gene. To assess the methylation status of the FMR1 gene promoter it was carried out a bisulphite sequencing analysis.Both FMR1-mRNA levels and DNA methylation were unmodified with respect to untreated controls.These results demonstrate that the AFQ056 effect on fully methylated FXS patients is not due to a secondary effect on DNA methylation and consequent transcriptional activation of FMR1.The fragile X syndrome (FXS, MIM #300624), the most common cause of inherited mental retardation, is due to the amplification (> 200 repeats) of a sequence of CGG triplets in the 5' UTR of the FMR1 gene, followed by methylation of cytosines, including those of the promoter upstream [1]. Although the coding region of the gene remains intact, the two changes, one structural and one epigenetic, lead to transcriptional silencing, and consequent absence of the FMRP protein, responsible for the manifestations of the syndrome. FMRP is an RNA-binding protein, which inhibits the translation of messenger RNAs (mRNAs), especially within post-synaptic vesicles of the dendritic spines of hippocampal neurons [2]. It has been demonstrated that the absence of FMRP causes an upregulation of metabotropic glutamate receptors 5 (mGluR5)-mediated signalling pathways, which is the probable cause of the behavioural and cognitive impairments observed in FXS patients [3]. In FXS animal models it was demonstrated that many aspects of the phenotype (behavioural abnormalities, learning deficit, altered dendritic spines, macroorchidism) may be due to excessive mGluR5 signalling. Indeed, crossing Fmr1 KO mice with heterozygous Grm5 KO mice, expressing reduced amounts of glutamate receptors, rescues many of the FXS phenotypes, except for mac

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