scholarly journals Mechanism of Repeat-Associated MicroRNAs in Fragile X Syndrome

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Karen Kelley ◽  
Shin-Ju E. Chang ◽  
Shi-Lung Lin
Keyword(s):  
Fragile X Syndrome ◽  
Metabotropic Glutamate Receptor ◽  
Trinucleotide Repeat ◽  
Fragile X ◽  
Protein Product ◽  
Repeat Expansion ◽  
Trinucleotide Repeats ◽  
Transgenic Zebrafish ◽  
Zebrafish Model ◽  
Triplet Repeat Expansion

The majority of the human genome is comprised of non-coding DNA, which frequently contains redundant microsatellite-like trinucleotide repeats. Many of these trinucleotide repeats are involved in triplet repeat expansion diseases (TREDs) such as fragile X syndrome (FXS). After transcription, the trinucleotide repeats can fold into RNA hairpins and are further processed byDicerendoribonuclases to form microRNA (miRNA)-like molecules that are capable of triggering targeted gene-silencing effects in the TREDs. However, the function of these repeat-associated miRNAs (ramRNAs) is unclear. To solve this question, we identified the first native ramRNA in FXS and successfully developed a transgenic zebrafish model for studying its function. Our studies showed that ramRNA-induced DNA methylation of theFMR15′-UTR CGG trinucleotide repeat expansion is responsible for both pathological and neurocognitive characteristics linked to the transcriptionalFMR1gene inactivation and the deficiency of its protein product FMRP. FMRP deficiency often causes synapse deformity in the neurons essential for cognition and memory activities, whileFMR1inactivation augments metabotropic glutamate receptor (mGluR)-activated long-term depression (LTD), leading to abnormal neuronal responses in FXS. Using this novel animal model, we may further dissect the etiological mechanisms of TREDs, with the hope of providing insights into new means for therapeutic intervention.

scholarly journals Urine microRNA Profiling Displays miR-125a Dysregulation in Children with Fragile X Syndrome

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 289
Author(s):  
Noora Putkonen ◽  
Asta Laiho ◽  
Doug Ethell ◽  
Juha Pursiheimo ◽  
Anna-Kaisa Anttonen ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Metabotropic Glutamate Receptor ◽  
Fragile X ◽  
Type I ◽  
Neuronal Function ◽  
Full Mutation ◽  
Treatment Target ◽  
Metabotropic Glutamate ◽  
Triplet Repeat Expansion ◽  
Premutation Allele

A triplet repeat expansion leading to transcriptional silencing of the FMR1 gene results in fragile X syndrome (FXS), which is a common cause of inherited intellectual disability and autism. Phenotypic variation requires personalized treatment approaches and hampers clinical trials in FXS. We searched for microRNA (miRNA) biomarkers for FXS using deep sequencing of urine and identified 28 differentially regulated miRNAs when 219 reliably identified miRNAs were compared in dizygotic twin boys who shared the same environment, but one had an FXS full mutation, and the other carried a premutation allele. The largest increase was found in miR-125a in the FXS sample, and the miR-125a levels were increased in two independent sets of urine samples from a total of 19 FXS children. Urine miR-125a levels appeared to increase with age in control subjects, but varied widely in FXS subjects. Should the results be generalized, it could suggest that two FXS subgroups existed. Predicted gene targets of the differentially regulated miRNAs are involved in molecular pathways that regulate developmental processes, homeostasis, and neuronal function. Regulation of miR-125a has been associated with type I metabotropic glutamate receptor signaling (mGluR), which has been explored as a treatment target for FXS, reinforcing the possibility that urine miR-125a may provide a novel biomarker for FXS.

scholarly journals Secondary structural choice of DNA and RNA associated with CGG/CCG trinucleotide repeat expansion rationalizes the RNA misprocessing in FXTAS

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yogeeshwar Ajjugal ◽  
Narendar Kolimi ◽  
Thenmalarchelvi Rathinavelan
Keyword(s):  
Rna Binding ◽  
Trinucleotide Repeat ◽  
Rna Binding Proteins ◽  
Fragile X ◽  
Repeat Expansion ◽  
Mobility Shift ◽  
Cgg Repeat ◽  
Dna And Rna ◽  
Structural Choice ◽  
Sense Strand

AbstractCGG tandem repeat expansion in the 5′-untranslated region of the fragile X mental retardation-1 (FMR1) gene leads to unusual nucleic acid conformations, hence causing genetic instabilities. We show that the number of G…G (in CGG repeat) or C…C (in CCG repeat) mismatches (other than A…T, T…A, C…G and G…C canonical base pairs) dictates the secondary structural choice of the sense and antisense strands of the FMR1 gene and their corresponding transcripts in fragile X-associated tremor/ataxia syndrome (FXTAS). The circular dichroism (CD) spectra and electrophoretic mobility shift assay (EMSA) reveal that CGG DNA (sense strand of the FMR1 gene) and its transcript favor a quadruplex structure. CD, EMSA and molecular dynamics (MD) simulations also show that more than four C…C mismatches cannot be accommodated in the RNA duplex consisting of the CCG repeat (antisense transcript); instead, it favors an i-motif conformational intermediate. Such a preference for unusual secondary structures provides a convincing justification for the RNA foci formation due to the sequestration of RNA-binding proteins to the bidirectional transcripts and the repeat-associated non-AUG translation that are observed in FXTAS. The results presented here also suggest that small molecule modulators that can destabilize FMR1 CGG DNA and RNA quadruplex structures could be promising candidates for treating FXTAS.

scholarly journals Behavioral and Synaptic Circuit Features in a Zebrafish Model of Fragile X Syndrome

PLoS ONE ◽  
2013 ◽  
Vol 8 (3) ◽  
pp. e51456 ◽  
Author(s):  
Ming-Chong Ng ◽  
Yi-Ling Yang ◽  
Kwok-Tung Lu
Keyword(s):  
Fragile X Syndrome ◽  
Fragile X ◽  
Zebrafish Model ◽  
Synaptic Circuit

scholarly journals Spatially coordinated heterochromatinization of distal short tandem repeats in fragile X syndrome

2021 ◽  
Author(s):  
Linda Zhou ◽  
Chunmin Ge ◽  
Thomas Malachowski ◽  
Ji Hun Kim ◽  
Keerthivasan Raanin Chandradoss ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Short Tandem Repeats ◽  
Tandem Repeats ◽  
Fragile X ◽  
Repeat Expansion ◽  
Genome Wide ◽  
A Genome ◽  
In Trans ◽  
Surveillance Mechanism ◽  
Short Tandem

AbstractShort tandem repeat (STR) instability is causally linked to pathologic transcriptional silencing in a subset of repeat expansion disorders. In fragile X syndrome (FXS), instability of a single CGG STR tract is thought to repress FMR1 via local DNA methylation. Here, we report the acquisition of more than ten Megabase-sized H3K9me3 domains in FXS, including a 5-8 Megabase block around FMR1. Distal H3K9me3 domains encompass synaptic genes with STR instability, and spatially co-localize in trans concurrently with FMR1 CGG expansion and the dissolution of TADs. CRISPR engineering of mutation-length FMR1 CGG to normal-length preserves heterochromatin, whereas cut-out to pre-mutation-length attenuates a subset of H3K9me3 domains. Overexpression of a pre-mutation-length CGG de-represses both FMR1 and distal heterochromatinized genes, indicating that long-range H3K9me3-mediated silencing is exquisitely sensitive to STR length. Together, our data uncover a genome-wide surveillance mechanism by which STR tracts spatially communicate over vast distances to heterochromatinize the pathologically unstable genome in FXS.One-Sentence SummaryHeterochromatinization of distal synaptic genes with repeat instability in fragile X is reversible by overexpression of a pre-mutation length CGG tract.

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