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Modulation of methylation in the FMR1 promoter region after long term treatment with L-carnitine and acetyl-L-carnitine
  1. E Pascale1,
  2. E Battiloro2,
  3. G Cimino Reale2,
  4. R Pietrobono3,
  5. M G Pomponi3,
  6. P Chiurazzi4,
  7. R Nicolai5,
  8. M Calvani5,
  9. G Neri3,
  10. E D’Ambrosio2
  1. 1Dipartimento di Medicina Molecolare e Patologia, Università di Roma “La Sapienza”, Italy
  2. 2Istituto di Neurobiologia e Medicina Molecolare, CNR, Rome, Italy
  3. 3Istituto di Genetica Medica, Università Cattolica, Rome, Italy
  4. 4Dipartimento di Pediatria, Policlinico Universitario, Messina, Italy
  5. 5Direzione Scientifica, Sigma-Tau SpA, Pomezia, Italy
  1. Correspondence:
 Dr E D’Ambrosio, Istituto di Neurobiologia e Medicina Molecolare, CNR, viale Marx 43, 00137 Roma, Italy;

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Fragile X syndrome (FXS) is a triplet repeat disorder caused by a large expansion of the CGG repeat in the 5′-untranslated region (UTR) of the fragile X mental retardation (FMR1) gene.1,2 Full mutation alleles are almost always associated with extensive hypermethylation of the repeat and of the upstream CpG island, which correlates with gene silencing and absence of the FMR1 protein. Cognitive function ranging from severe mental retardation to learning disabilities are found in affected people of both sexes. Many mildly affected people show “mosaic” methylation at the FMR1 promoter.3,4 Unusual alleles carrying a completely or partially unmethylated full mutation have been described.5,6 It was shown that in male patients with FXS with unmethylated alleles in the full mutation range, the FMR1 mRNA level is higher than in normal controls. This finding shows that upregulation of the FMR1 gene occurs in cells with unmethylated full mutation alleles and that the CGG triplet expansion does not suppress transcription directly.7 Thus, abnormal hypermethylation of the FMR1 promoter suppresses gene transcription. This hypothesis is also supported by the ability of 5-azadeoxycytidine (5-azadC) to restore the FMR1 gene expression in lymphoblastoid cell lines from patients with non-mosaic full mutation FXS by inducing DNA demethylation.8,9

The silencing of the hypermethylated FMR1 gene is consistent with a model in which methylation is coupled with the histone acetylation state. It has been found that the 5′ end of the FMR1 gene of patients with FXS is associated with deacetylated histones H3 and H410 and that the treatment of fragile X cells with 5-azadC results in the reassociation of acetylated histones with the FMR1 promoter and transcriptional reactivation. This finding suggests that both methylation and histone deacetylation are linked to transcriptional inactivity.10,11 In fact, it has …

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