In Vitro Reactivation of the FMR1 Gene Involved in Fragile X Syndrome (original) (raw)

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Istituto di Genetica Medica, Università Cattolica, and Centro Ricerche per la Disabilità Mentale e Motoria, Associazione Anni Verdi

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Largo F. Vito 1, 00168 Rome, Italy

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Istituto di Genetica Medica, Università Cattolica, and Centro Ricerche per la Disabilità Mentale e Motoria, Associazione Anni Verdi

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Largo F. Vito 1, 00168 Rome, Italy

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1

Department of Clinical Genetics, Erasmus University

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Rotterdam, The Netherlands

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Department of Clinical Genetics, Erasmus University

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Rotterdam, The Netherlands

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Istituto di Genetica Medica, Università Cattolica, and Centro Ricerche per la Disabilità Mentale e Motoria, Associazione Anni Verdi

,

Largo F. Vito 1, 00168 Rome, Italy

*To whom correspondence should be addressed. Tel: +39 6 30154606; Fax: +39 6 3050031; Email: ibige@rm.unicatt.it

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Received:

04 September 1997

Accepted:

23 October 1997

Published:

01 January 1998

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Pietro Chiurazzi, M. Grazia Pomponi, Rob Willemsen, Ben A. Oostra, Giovanni Neri, In Vitro Reactivation of the FMR1 Gene Involved in Fragile X Syndrome, Human Molecular Genetics, Volume 7, Issue 1, January 1998, Pages 109–113, https://doi.org/10.1093/hmg/7.1.109
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Abstract

Fragile X syndrome is the most frequent cause of heritable mental retardation. Most patients have a mutation in the 5′ untranslated region of the FMR1 gene, consisting of the amplification of a polymorphic (CGG)n repeat sequence, and cytogenetically express the folate-sensitive fragile site FRAXA in Xq27.3. Fragile X patients harbour an expanded sequence with >200 CGG repeats (full mutation), accompanied by methylation of most cytosines of the sequence itself and of the upstream CpG island. This abnormal hypermethylation of the promoter suppresses gene transcription, resulting in the absence of the FMR1 protein. Rare individuals of normal intelligence were shown to carry a completely or partially unmethylated full mutation and to express the FMR1 protein. Given this observation and knowing that the open reading frame of the mutated FMR1 gene is intact, we decided to investigate whether its activity could be restored in vitro by inducing DNA demethylation with 5-azadeoxycytidine (5-azadC) in fragile X patients' lymphoblastoid cells. We report that treatment with 5-azadC causes reactivation of fully mutated FMR1 genes with 300–800 repeats, as shown by the restoration of specific mRNA and protein production. This effect correlates with the extent of promoter demethylation, determined by restriction analysis with methylation-sensitive enzymes. These results confirm the critical role of FMR1 promoter hypermethylation in the pathogenesis of the fragile X syndrome, provide an additional explanation for the normal IQ of the rare males with unmethylated full mutations and pave the way to future attempts at pharmacologically restoring mutant FMR1 gene activity in vivo.

© 1998 Oxford University Press

Topic:

• transcription, genetic
• mutation
• folic acid
• fragile x syndrome
• cpg islands
• dna
• intelligence
• intellectual disability
• methylation
• open reading frames
• rna, messenger
• untranslated regions
• enzymes
• decitabine
• hypermethylation
• amplification
• fmr1 gene
• demethylation

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