scholarly journals DNA Methylation, Mechanisms of FMR1 Inactivation and Therapeutic Perspectives for Fragile X Syndrome

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 296
Author(s):  
Veronica Nobile ◽  
Cecilia Pucci ◽  
Pietro Chiurazzi ◽  
Giovanni Neri ◽  
Elisabetta Tabolacci
Keyword(s):  
Dna Methylation ◽  
Fragile X Syndrome ◽  
Intellectual Development ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Fragile X ◽  
Fmr1 Gene ◽  
Critical Question ◽  
Cgg Repeat

Among the inherited causes of intellectual disability and autism, Fragile X syndrome (FXS) is the most frequent form, for which there is currently no cure. In most FXS patients, the FMR1 gene is epigenetically inactivated following the expansion over 200 triplets of a CGG repeat (FM: full mutation). FMR1 encodes the Fragile X Mental Retardation Protein (FMRP), which binds several mRNAs, mainly in the brain. When the FM becomes methylated at 10–12 weeks of gestation, the FMR1 gene is transcriptionally silent. The molecular mechanisms involved in the epigenetic silencing are not fully elucidated. Among FXS families, there is a rare occurrence of males carrying a FM, which remains active because it is not methylated, thus ensuring enough FMRPs to allow for an intellectual development within normal range. Which mechanisms are responsible for sparing these individuals from being affected by FXS? In order to answer this critical question, which may have possible implications for FXS therapy, several potential epigenetic mechanisms have been described. Here, we focus on current knowledge about the role of DNA methylation and other epigenetic modifications in FMR1 gene silencing.

scholarly journals Small Molecules Targeting H3K9 Methylation Prevent Silencing of Reactivated FMR1 Alleles in Fragile X Syndrome Patient Derived Cells

Genes ◽  
2020 ◽  
Vol 11 (4) ◽  
pp. 356 ◽  
Author(s):  
Daman Kumari ◽  
Nicholas Sciascia ◽  
Karen Usdin
Keyword(s):  
Dna Methylation ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Fmr1 Gene ◽  
Mrna Levels ◽  
H3k9 Methylation ◽  
Methyl Transferase ◽  
Cgg Repeat ◽  
Heterochromatin Formation ◽  
Gene Reactivation

In fragile X syndrome (FXS), expansion of a CGG repeat tract in the 5′-untranslated region of the FMR1 gene to >200 repeats causes transcriptional silencing by inducing heterochromatin formation. Understanding the mechanism of FMR1 silencing is important as gene reactivation is a potential treatment approach for FXS. To date, only the DNA demethylating drug 5-azadeoxycytidine (AZA) has proved effective at gene reactivation; however, this drug is toxic. The repressive H3K9 methylation mark is enriched on the FMR1 gene in FXS patient cells and is thus a potential druggable target. However, its contribution to the silencing process is unclear. Here, we studied the effect of small molecule inhibitors of H3K9 methylation on FMR1 expression in FXS patient cells. Chaetocin showed a small effect on FMR1 gene reactivation and a synergistic effect on FMR1 mRNA levels when used in combination with AZA. Additionally, chaetocin, BIX01294 and 3-Deazaneplanocin A (DZNep) were able to significantly delay the re-silencing of AZA-reactivated FMR1 alleles. These data are consistent with the idea that H3K9 methylation precedes DNA methylation and that removal of DNA methylation is necessary to see the optimal effect of histone methyl-transferase (HMT) inhibitors on FMR1 gene expression. Nonetheless, our data also show that drugs targeting repressive H3K9 methylation marks are able to produce sustained reactivation of the FMR1 gene after a single dose of AZA.

scholarly journals Reversion to Normal of FMR1 Expanded Alleles: A Rare Event in Two Independent Fragile X Syndrome Families

Genes ◽  
2020 ◽  
Vol 11 (3) ◽  
pp. 248
Author(s):  
Elisabetta Tabolacci ◽  
Roberta Pietrobono ◽  
Giulia Maneri ◽  
Laura Remondini ◽  
Veronica Nobile ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Binding Sites ◽  
Molecular Mechanisms ◽  
Fragile X ◽  
Rare Event ◽  
The Other ◽  
Fmr1 Gene ◽  
Full Mutation ◽  
Cgg Repeat ◽  
Agg Interruptions

Fragile X syndrome (FXS) is mostly due to the expansion and subsequent methylation of a polymorphic CGG repeat in the 5’ UTR of the FMR1 gene. Full mutation alleles (FM) have more than 200 repeats and result in FMR1 gene silencing and FXS. FMs arise from maternal premutations (PM) that have 56–200 CGGs; contractions of a maternal PM or FM are rare. Here, we describe two unaffected boys in two independent FXS families who inherited a non-mosaic allele in the normal and intermediate range, respectively, from their mothers who are carriers of an expanded CGG allele. The first boy inherited a 51 CGG allele (without AGG interruptions) from his mother, who carries a PM allele with 72 CGGs. The other boy inherited from his FM mother an unusual allele with 19 CGGs resulting from a deletion, removing 85 bp upstream of the CGG repeat. Given that transcription of the deleted allele was found to be preserved, we assume that the binding sites for FMR1 transcription factors are excluded from the deletion. Such unusual cases resulting in non-mosaic reduction of maternal CGG expansions may help to clarify the molecular mechanisms underlying the instability of the FMR1 gene.

A Novel Polymorphism in the FMR1 Gene: Implications for Clinical Testing of Fragile X Syndrome

2008 ◽  
Vol 132 (1) ◽  
pp. 95-98
Author(s):  
Bharat Thyagarajan ◽  
Matthew Bower ◽  
Michael Berger ◽  
Sidney Jones ◽  
Michelle Dolan ◽  
...  
Keyword(s):  
Polymerase Chain Reaction ◽  
Mental Retardation ◽  
Fragile X Syndrome ◽  
Southern Blot ◽  
Trinucleotide Repeat ◽  
Fragile X ◽  
Fmr1 Gene ◽  
Chain Reaction ◽  
Cgg Repeat ◽  
Polymerase Chain

Abstract Fragile X syndrome is the most common cause of inherited mental retardation among males. In most cases, the molecular basis of fragile X syndrome is the expansion and subsequent methylation of a CGG trinucleotide repeat in the 5′ untranslated region of the fragile X mental retardation 1 (FMR1) gene. Laboratory diagnosis usually relies on a combination of Southern blot and polymerase chain reaction analyses. In this case report we describe an unusual Southern blot result in a patient who presented with developmental delay and had a normal CGG repeat number by polymerase chain reaction analysis. Further investigation revealed a novel G3310C transversion in the FMR1 gene resulting in a new recognition site for the BssHII restriction enzyme. This novel restriction site could potentially mimic a partial deletion of the FMR1 gene on Southern blot analysis and thus represents a possible pitfall in the diagnosis of fragile X syndrome.

scholarly journals The Implication of AMPA Receptor in Synaptic Plasticity Impairment and Intellectual Disability in Fragile X Syndrome

2017 ◽  
pp. 715-727 ◽  
Author(s):  
G.-R. CHENG ◽  
X.-Y. LI ◽  
Y.-D. XIANG ◽  
D. LIU ◽  
S. M. MCCLINTOCK ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Intellectual Disability ◽  
Fragile X Syndrome ◽  
Ampa Receptors ◽  
Molecular Mechanisms ◽  
Neuronal Development ◽  
Current Knowledge ◽  
Fragile X ◽  
Single Gene ◽  
Poor Mental Health

Fragile X syndrome (FXS) is the most frequently inherited form of intellectual disability and prevalent single-gene cause of autism. A priority of FXS research is to determine the molecular mechanisms underlying the cognitive and social functioning impairments in humans and the FXS mouse model. Glutamate ionotropic alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPARs) mediate a majority of fast excitatory neurotransmission in the central nervous system and are critically important for nearly all aspects of brain function, including neuronal development, synaptic plasticity, and learning and memory. Both preclinical and clinical studies have indicated that expression, trafficking, and functions of AMPARs are altered and result in altered synapse development and plasticity, cognitive impairment, and poor mental health in FXS. In this review, we discuss the contribution of AMPARs to disorders of FXS by highlighting recent research advances with a specific focus on change in AMPARs expression, trafficking, and dependent synaptic plasticity. Since changes in synaptic strength underlie the basis of learning, development, and disease, we suggest that the current knowledge base of AMPARs has reached a unique point to permit a comprehensive re-evaluation of their roles in FXS.

scholarly journals DNA Hypermethylation and Unstable Repeat Diseases: A Paradigm of Transcriptional Silencing to Decipher the Basis of Pathogenic Mechanisms

Genes ◽  
2020 ◽  
Vol 11 (6) ◽  
pp. 684
Author(s):  
Loredana Poeta ◽  
Denise Drongitis ◽  
Lucia Verrillo ◽  
Maria Giuseppina Miano
Keyword(s):  
Dna Methylation ◽  
Molecular Mechanisms ◽  
Tandem Repeats ◽  
Fragile X ◽  
Neuromuscular Diseases ◽  
Transcriptional Silencing ◽  
Common Disease ◽  
Dna Hypermethylation ◽  
Disease Modifier

Unstable repeat disorders comprise a variable group of incurable human neurological and neuromuscular diseases caused by an increase in the copy number of tandem repeats located in various regions of their resident genes. It has become clear that dense DNA methylation in hyperexpanded non-coding repeats induces transcriptional silencing and, subsequently, insufficient protein synthesis. However, the ramifications of this paradigm reveal a far more profound role in disease pathogenesis. This review will summarize the significant progress made in a subset of non-coding repeat diseases demonstrating the role of dense landscapes of 5-methylcytosine (5mC) as a common disease modifier. However, the emerging findings suggest context-dependent models of 5mC-mediated silencing with distinct effects of excessive DNA methylation. An in-depth understanding of the molecular mechanisms underlying this peculiar group of human diseases constitutes a prerequisite that could help to discover novel pathogenic repeat loci, as well as to determine potential therapeutic targets. In this regard, we report on a brief description of advanced strategies in DNA methylation profiling for the identification of unstable Guanine-Cytosine (GC)-rich regions and on promising examples of molecular targeted therapies for Fragile X disease (FXS) and Friedrich ataxia (FRDA) that could pave the way for the application of this technique in other hypermethylated expansion disorders.

scholarly journals Mosaicism for the fragile X syndrome full mutation and deletions within the CGG repeat of the FMR1 gene.

1996 ◽  
Vol 33 (4) ◽  
pp. 338-340 ◽  
Author(s):  
M Mila ◽  
S Castellvi-Bel ◽  
A Sanchez ◽  
C Lazaro ◽  
M Villa ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Fragile X ◽  
Fmr1 Gene ◽  
Full Mutation ◽  
Cgg Repeat
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