What Mechanisms Induce Methylation of FMR1 Gene Full Mutation? A Still Unanswered Question

  • Elisabetta Tabolacci
  • Giovanni NeriEmail author
Part of the Epigenetics and Human Health book series (EHH)


The fragile X syndrome (FXS) is the most frequent form of inherited intellectual disability and autism, for which there is currently no cure. In the vast majority of FXS patients, the FMR1 gene is inactivated by epigenetic changes secondary to expansion of a CGG repeat. FMR1 encodes the fragile X mental retardation protein (FMRP) involved in multiple aspects of mRNA metabolism in the brain. Many mRNAs that are dysregulated in the absence of FMRP encode synaptic proteins, causing a characteristically abnormal morphogenesis of dendritic spines. Methylation of FMR1 full mutation is estimated to occur around 10–12 weeks of gestation, resulting in block of transcription. The molecular mechanisms involved in this particular type of methylation are still unknown. Amidst fragile X families, there are rare males who, in spite of having inherited a full mutation (usually of small dimensions between 200 and 300 CGG repeats), are unable to methylate it. These individuals produce enough FMRP protein to allow an intellectual development within normal range. What factors are responsible for the rescue of these individuals from being affected with the fragile X syndrome? In an effort to answer this crucial question, which may have consequences for a cure, several potential regulatory factors have been studied so far. The identification of molecular and cellular pathways underlying the pathogenesis of FXS that may be targetable by drugs with potential therapeutic value remains the ultimate goal. Here we produce a critical revision of the present knowledge about the syndrome and its epigenetic pathogenesis.


Fragile X syndrome FMR1 gene DNA methylation Epigenetic modifications FMRP 


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Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Institute of Genomic Medicine, School of MedicineCatholic UniversityRomeItaly

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