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Genes 2016, 7(8), 49; doi:10.3390/genes7080049

Transcriptional Reactivation of the FMR1 Gene. A Possible Approach to the Treatment of the Fragile X Syndrome

Institute of Genomic Medicine, School of Medicine, Catholic University, Largo Francesco Vito 1, Rome 00168, Italy
The authors would like to dedicate this paper to the memory of Maria Giulia Torrioli, a child neuropsychiatrist and a recognized leader in the care and treatment of children with FXS.
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Author to whom correspondence should be addressed.
Academic Editor: Mark Hirst
Received: 21 June 2016 / Revised: 29 July 2016 / Accepted: 9 August 2016 / Published: 17 August 2016
(This article belongs to the Special Issue Fragile X Syndrome)
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Abstract

Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability, caused by CGG expansion over 200 repeats (full mutation, FM) at the 5′ untranslated region (UTR) of the fragile X mental retardation 1 (FMR1) gene and subsequent DNA methylation of the promoter region, accompanied by additional epigenetic histone modifications that result in a block of transcription and absence of the fragile X mental retardation protein (FMRP). The lack of FMRP, involved in multiple aspects of mRNA metabolism in the brain, is thought to be the direct cause of the FXS phenotype. Restoration of FMR1 transcription and FMRP production can be obtained in vitro by treating FXS lymphoblastoid cell lines with the demethylating agent 5-azadeoxycytidine, demonstrating that DNA methylation is key to FMR1 inactivation. This concept is strengthened by the existence of rare male carriers of a FM, who are unable to methylate the FMR1 promoter. These individuals produce limited amounts of FMRP and are of normal intelligence. Their inability to methylate the FMR1 promoter, whose cause is not yet fully elucidated, rescues them from manifesting the FXS. These observations demonstrate that a therapeutic approach to FXS based on the pharmacological reactivation of the FMR1 gene is conceptually tenable and worthy of being further pursued. View Full-Text
Keywords: Fragile X syndrome; FMR1 gene; epigenetic therapy; DNA methylation; histone modifications; drug treatments Fragile X syndrome; FMR1 gene; epigenetic therapy; DNA methylation; histone modifications; drug treatments
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Tabolacci, E.; Palumbo, F.; Nobile, V.; Neri, G. Transcriptional Reactivation of the FMR1 Gene. A Possible Approach to the Treatment of the Fragile X Syndrome. Genes 2016, 7, 49.

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