An antisense transcript spanning the CGG repeat region of FMR1 is upregulated in premutation carriers but silenced in full mutation individuals

Ladd, Paula D.; Smith, Leslie E.; Rabaia, Natalia A.; Moore, James M.; Georges, Sara A.; Hansen, R. Scott; Hagerman, Randi J.; Tassone, Flora; Tapscott, Stephen J.; Filippova, Galina N.

doi:10.1093/hmg/ddm293

Cited by 237 publications

(269 citation statements)

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“…The ASFMR1 gene promoter is located within intron 2 of the FMR1 gene. 21 Interestingly, the expression of ASFMR1, similar to that of FMR1, is elevated in fragile X premutation carriers and decreased in individuals with full mutation alleles. 21 To date, translation of the ASFMR1 gene has not been reported, and whether it has a pathogenic role is not known.…”

Section: Discussionmentioning

confidence: 99%

De novo microduplication of the FMR1 gene in a patient with developmental delay, epilepsy and hyperactivity

et al. 2012

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Loss-of-function due to expansion of a CGG repeat located in the 5'UTR of the FMR1 gene is the most frequent cause of fragile X syndrome. Less than 1% of individuals with fragile X syndrome have been reported to have a partial or full deletion or point mutation of the FMR1 gene. However, whether a copy number gain of the FMR1 gene could result in certain clinical phenotypes has not been fully investigated. Here, we report the case of a child who presented with developmental delay starting at 9 months of age, fine motor and speech delay, progressive seizures since 18 months of age and hyperactivity. Molecular workup identified a de novo microduplication in the Xq27.3 region, including the FMR1 gene and the ASFMR1 gene. The expression level of the FMR1 gene in peripheral blood did not differ from that of the controls. In addition, an inherited 363-kb duplication on the chromosome 1q44 region and an inherited deletion of 168 kb on the chromosome 4p15.31 region were detected. It is not clear whether these inherited copy number variations (CNVs) also have a modifying role in the clinical phenotype of this patient.

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Section: Discussionmentioning

confidence: 99%

De novo microduplication of the FMR1 gene in a patient with developmental delay, epilepsy and hyperactivity

et al. 2012

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“…A second model, "RAN translation", represents noncanonical translation that results in expression of toxic polyglycine-and polyalanine-containing products (128,129). A third model, "antisense FMR1 (ASFMR1) toxicity", involves the expression of antisense transcripts products (130). Mitochondrial abnormalities have also been found in FXS and premutation carriers.…”

Section: Premutation Genotypesmentioning

confidence: 99%

Fragile X spectrum disorders

Lozano

Rosero²,

Hagerman

2014

IRDR

156

110

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“…CTCF (CCCTC-binding factor), the first insulator protein found in mammals, is among the nuclear proteins binding the methylation boundary. CTCF also binds to the promoter and intron 2 of the FMR1 gene [Ladd et al, 2007]. We recently investigated the role of CTCF on FMR1 transcription and observed that CTCF depletion did not cause spreading of methylation over the FMR1 promoter of UFM cell lines, in spite of the presence of the CGG expansion in the full mutation range [Lanni et al, 2013].…”

Section: Fragile X Syndromementioning

confidence: 99%

“…These can be generated by processing longer double-stranded RNAs formed by complementary pairing of mRNAs and long antisense transcripts due to bidirectional transcription at the same locus [Morris, 2009]. The presence of long ncRNAs overlapping (at least in part) critical mRNAs has been proven in several imprinted loci such as those of Angelman and Beckwith-Wiedemann syndromes [Rougeulle et al, 1998;Lee et al, 1999] as well as those of Fragile X [Ladd et al, 2007;Chen et al, 2008;De Biase et al, 2009]. It is assumed that double-stranded RNAs are processed by the RNAi machinery into siRNAs that induce either degradation of complementary mRNAs (post-transcriptional gene silencing) or cause RNA-mediated DNA methylation (transcriptional gene silencing).…”

Section: Rna Transcriptsmentioning

confidence: 99%

“…We suggested that CTCF may stabilize a chromatin loop between sense and antisense transcriptional regulatory regions (located in the promoter and intron 2, respectively). In fact, coordinated bidirectional transcription has been demonstrated at the active FMR1 locus, overlapping the CGG repeats and exon 1 of the gene [Ladd et al, 2007]. Similar to FMR1, the antisense transcript (ASFMR1) is upregulated in individuals with premutations and is not expressed in full mutation alleles.…”

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Epigenetics, fragile X syndrome and transcriptional therapy

Tabolacci

Chiurazzi

2013

American J of Med Genetics Pt A

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Epigenetics refers to the study of heritable changes in gene expression that occur without a change in DNA sequence. Epigenetic mechanisms therefore include all transcriptional controls that determine how genes are expressed during development and differentiation, but also in individual cells responding to environmental stimuli. The purpose of this review is to examine the basic principles of epigenetic mechanisms and their contribution to human disorders with a particular focus on fragile X syndrome (FXS), the most common monogenic form of developmental cognitive impairment. FXS represents a prototype of the so-called repeat expansion disorders due to "dynamic" mutations, namely the expansion (known as "full mutation") of a CGG repeat in the 5 0 UTR of the FMR1 gene. This genetic anomaly is accompanied by epigenetic modifications (mainly DNA methylation and histone deacetylation), resulting in the inactivation of the FMR1 gene. The presence of an intact FMR1 coding sequence allowed pharmacological reactivation of gene transcription, particularly through the use of the DNA demethylating agent 5 0 -aza-2 0 -deoxycytydine and/or inhibitors of histone deacetylases. These treatments suggested that DNA methylation is dominant over histone acetylation in silencing the FMR1 gene. The importance of DNA methylation in repressing FMR1 transcription is confirmed by the existence of rare unaffected males carrying unmethylated full mutations. Finally, we address the potential use of epigenetic approaches to targeted treatment of other genetic conditions. Ó 2013 Wiley Periodicals, Inc.Key words: fragile X syndrome; epigenetics; transcriptional therapy INTRODUCTION When in 1942 Conrad H. Waddington coined the term "epigenetics," the exact nature of genes and their role in heredity and in transcriptional regulation was not known; he used it as a conceptual model of how genes might interact with their surroundings to produce a phenotype [Waddington, 1942]. The term is a portmanteau of the words epigenesis (differentiation of cells from their initial totipotent state in embryonic development) and genetics. Only in 2008 at a Cold Spring harbor meeting, consensus was reached on the definition of epigenetic trait, as "stably heritable phenotype resulting from changes in a chromosome without alterations in the DNA sequence" [Berger et al., 2009]. The greek prefix epi-refers to features that are "on top of" genetics, that is, all those stable but reversible changes to DNA, RNA and proteins that regulate gene expression and allow cells with the same DNA to do different things at different times.Broadly speaking, epigenetic mechanisms include all transcriptional controls that regulate gene expression, whether during development and differentiation or in mature cells responding to the environment. Epigenetic changes can be inherited (e.g., imprinting) and be relatively stable (e.g., chromosome X inactivation), but are often rapidly imposed or removed on a given locus according to cell needs. Four major layers of epigenetic controls have ...

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An antisense transcript spanning the CGG repeat region of FMR1 is upregulated in premutation carriers but silenced in full mutation individuals

Cited by 237 publications

References 53 publications

De novo microduplication of the FMR1 gene in a patient with developmental delay, epilepsy and hyperactivity

De novo microduplication of the FMR1 gene in a patient with developmental delay, epilepsy and hyperactivity

Fragile X spectrum disorders

Epigenetics, fragile X syndrome and transcriptional therapy

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