Home            Fragile X premutations: pathogenic mechanism
Chromatin remodelling resulting from FraX premutation alleles
Fragile X syndrome is known to result from transcriptional silencing of the FMR1 gene.
This results from hypermethylation of the CGG repeat tract in the 5' untranslated region of FMR1, that occurswhen there is a large expansion of that repeat tract.

In contrast, smaller expansions of the tract, as in "premutations", cause the fragile X tremor ataxia syndrome (FXTAS). It is known that this results from overexpression (rather than the under-expression caused by hypermethylation) of the FMR1 gene, resulting in increased (and toxic) levels of the transcript.
Until now, the mechanism of overexpression of the gene that is associated with the premutations has not been explained.

Experiments in a Drosophila model of FXTAS, and in human premutation cell lines, have now shown that the premutation alleles cause increased histone acetylation at the CGG repeat and that this results in the increased FMR1 gene transcription.
For further information, see:
Histone Deacetylases Suppress CGG Repeat–Induced Neurodegeneration Via Transcriptional Silencing in Models of Fragile X Tremor Ataxia Syndrome
FMR1 geneschematic diagram from