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The mGluR5 antagonist AFQ056 does not affect methylation and transcription of the mutant FMR1 gene in vitro
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The mGluR5 antagonist AFQ056 does not affect methylation and transcription of the mutant FMR1 gene in vitro
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Journal Article
The mGluR5 antagonist AFQ056 does not affect methylation and transcription of the mutant FMR1 gene in vitro
2012
Overview
Background
Fragile X syndrome (FXS), the leading cause of inherited mental retardation, is due to expansion and methylation of a CGG sequence in the
FMR1
gene, which result in its silencing and consequent absence of FMRP protein. This absence causes loss of repression of metabotropic glutamate receptor 5 (mGluR5)-mediated pathways resulting in the behavioral and cognitive impairments associated with FXS. In a randomized, double-blind trial it was recently demonstrated a beneficial effect of AFQ056, a selective inhibitor of metabotrobic glutamate receptor type 5 (mGluR5), on fully methylated FXS patients respect to partially methylated FXS ones.
Methods
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.
Results
Both
FMR1
-mRNA levels and DNA methylation were unmodified with respect to untreated controls.
Conclusions
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
.
Publisher
BioMed Central,BioMed Central Ltd,BMC
