scholarly journals Abundancy of polymorphic CGG repeats in the human genome suggest a broad involvement in neurological disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Dale J. Annear ◽  
Geert Vandeweyer ◽  
Ellen Elinck ◽  
Alba Sanchis-Juan ◽  
Courtney E. French ◽  
...  
Keyword(s):  
Human Disease ◽  
Fragile X ◽  
Disease Genes ◽  
Cgg Repeat ◽  
Neurodevelopmental Disease ◽  
Repeat Units ◽  
Cgg Repeats ◽  
Repeat Expansions ◽  
Ataxia Syndrome ◽  
Strong Candidate

AbstractExpanded CGG-repeats have been linked to neurodevelopmental and neurodegenerative disorders, including the fragile X syndrome and fragile X-associated tremor/ataxia syndrome (FXTAS). We hypothesized that as of yet uncharacterised CGG-repeat expansions within the genome contribute to human disease. To catalogue the CGG-repeats, 544 human whole genomes were analyzed. In total, 6101 unique CGG-repeats were detected of which more than 93% were highly variable in repeat length. Repeats with a median size of 12 repeat units or more were always polymorphic but shorter repeats were often polymorphic, suggesting a potential intergenerational instability of the CGG region even for repeats units with a median length of four or less. 410 of the CGG repeats were associated with known neurodevelopmental disease genes or with strong candidate genes. Based on their frequency and genomic location, CGG repeats may thus be a currently overlooked cause of human disease.

scholarly journals CGG repeat RNA G-quadruplexes interact with FMRpolyG to cause neuronal dysfunction in fragile X-related tremor/ataxia syndrome

2021 ◽  
Vol 7 (3) ◽  
pp. eabd9440
Author(s):  
Sefan Asamitsu ◽  
Yasushi Yabuki ◽  
Susumu Ikenoshita ◽  
Kosuke Kawakubo ◽  
Moe Kawasaki ◽  
...  
Keyword(s):  
Therapeutic Strategy ◽  
Aminolevulinic Acid ◽  
Fragile X ◽  
Protoporphyrin Ix ◽  
Neuronal Dysfunction ◽  
Cgg Repeat ◽  
Repeat Expansions ◽  
Ataxia Syndrome ◽  
And Behavior ◽  
Ran Translation

Fragile X-related tremor/ataxia syndrome (FXTAS) is a neurodegenerative disease caused by CGG triplet repeat expansions in FMR1, which elicit repeat-associated non-AUG (RAN) translation and produce the toxic protein FMRpolyG. We show that FMRpolyG interacts with pathogenic CGG repeat-derived RNA G-quadruplexes (CGG-G4RNA), propagates cell to cell, and induces neuronal dysfunction. The FMRpolyG polyglycine domain has a prion-like property, preferentially binding to CGG-G4RNA. Treatment with 5-aminolevulinic acid, which is metabolized to protoporphyrin IX, inhibited RAN translation of FMRpolyG and CGG-G4RNA–induced FMRpolyG aggregation, ameliorating aberrant synaptic plasticity and behavior in FXTAS model mice. Thus, we present a novel therapeutic strategy to target G4RNA prionoids.

scholarly journals Mechanisms of Genome Instability in the Fragile X-Related Disorders

Genes ◽  
2021 ◽  
Vol 12 (10) ◽  
pp. 1633
Author(s):  
Bruce E. Hayward ◽  
Karen Usdin
Keyword(s):  
Genome Instability ◽  
Fragile Site ◽  
Fragile X ◽  
Fmr1 Gene ◽  
Cgg Repeat ◽  
Cgg Repeats ◽  
Large Numbers ◽  
Structural Abnormalities ◽  
Chromosomal Fragility ◽  
Ataxia Syndrome

The Fragile X-related disorders (FXDs), which include the intellectual disability fragile X syndrome (FXS), are disorders caused by expansion of a CGG-repeat tract in the 5′ UTR of the X-linked FMR1 gene. These disorders are named for FRAXA, the folate-sensitive fragile site that localizes with the CGG-repeat in individuals with FXS. Two pathological FMR1 allele size classes are distinguished. Premutation (PM) alleles have 54–200 repeats and confer the risk of fragile X-associated tremor/ataxia syndrome (FXTAS) and fragile X-associated primary ovarian insufficiency (FXPOI). PM alleles are prone to both somatic and germline expansion, with female PM carriers being at risk of having a child with >200+ repeats. Inheritance of such full mutation (FM) alleles causes FXS. Contractions of PM and FM alleles can also occur. As a result, many carriers are mosaic for different sized alleles, with the clinical presentation depending on the proportions of these alleles in affected tissues. Furthermore, it has become apparent that the chromosomal fragility of FXS individuals reflects an underlying problem that can lead to chromosomal numerical and structural abnormalities. Thus, large numbers of CGG-repeats in the FMR1 gene predisposes individuals to multiple forms of genome instability. This review will discuss our current understanding of these processes.

scholarly journals Evidence of mitochondrial dysfunction in fragile X-associated tremor/ataxia syndrome

2010 ◽  
Vol 429 (3) ◽  
pp. 545-552 ◽  
Author(s):  
Catherine Ross-Inta ◽  
Alicja Omanska-Klusek ◽  
Sarah Wong ◽  
Cedrick Barrow ◽  
Dolores Garcia-Arocena ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Fragile X ◽  
Mitochondrial Protein ◽  
Additional Treatment ◽  
Cgg Repeat ◽  
Cgg Repeats ◽  
Nitrative Stress ◽  
Ataxia Syndrome

FXTAS (fragile X-associated tremor/ataxia syndrome) is a late-onset neurodegenerative disorder that affects individuals who are carriers of premutation expansions (55–200 CGG repeats) in the 5′ untranslated region of the FMR1 (fragile X mental retardation 1) gene. The role of MD (mitochondrial dysfunction) in FXTAS was evaluated in fibroblasts and brain samples from premutation carriers with and without FXTAS symptoms, with a range of CGG repeats. This study resulted in several important conclusions: (i) decreased NAD- and FAD-linked oxygen uptake rates and uncoupling between electron transport and synthesis of ATP were observed in fibroblasts from premutation carriers; (ii) a lower expression of mitochondrial proteins preceded both in age and in CGG repeats the appearance of overt clinical involvement; (iii) the CGG repeat size required for altered mitochondrial protein expression was also smaller than that required to produce brain intranuclear inclusions from individuals with the premutation who died, suggesting that MD is an incipient pathological process occurring in individuals who do not display overt features of FXTAS; and (iv) on the basis of the CGG repeats, MD preceded the increase in oxidative/nitrative stress damage, indicating that the latter is a late event. MD in carriers of small CGG repeats, even when the allele size is not sufficient to produce FXTAS, may predispose them to other disorders (e.g. Parkinson's disease) that are likely to involve MD, and to environmental stressors, which may trigger the development of FXTAS symptoms. Detection of MD is of critical importance to the management of FXTAS, since it opens up additional treatment options for this disorder.

scholarly journals Neuroimaging Insight Into Fragile X-Associated Neuropsychiatric Disorders: Literature Review

2021 ◽  
Vol 12 ◽  
Author(s):  
Andrea Elias-Mas ◽  
Maria Isabel Alvarez-Mora ◽  
Conxita Caro-Benito ◽  
Laia Rodriguez-Revenga
Keyword(s):  
Brain Function ◽  
Psychiatric Symptoms ◽  
Fragile X ◽  
Clinical Manifestations ◽  
Neuropsychiatric Disorders ◽  
Psychiatric Symptomatology ◽  
Cgg Repeat ◽  
Cgg Repeats ◽  
Ataxia Syndrome ◽  
Insight Into

FMR1 premutation is defined by 55–200 CGG repeats in the Fragile X Mental Retardation 1 (FMR1) gene. FMR1 premutation carriers are at risk of developing a neurodegenerative disease called fragile X-associated tremor/ataxia syndrome (FXTAS) and Fragile X-associated primary ovarian insufficiency (FXPOI) in adulthood. In the last years an increasingly board spectrum of clinical manifestations including psychiatric disorders have been described as occurring at a greater frequency among FMR1 premutation carriers. Herein, we reviewed the neuroimaging findings reported in relation with psychiatric symptomatology in adult FMR1 premutation carriers. A structured electronic literature search was conducted on FMR1 premutation and neuroimaging yielding a total of 3,229 articles examined. Of these, 7 articles were analyzed and are included in this review. The results showed that the main radiological findings among adult FMR1 premutation carriers presenting neuropsychiatric disorders were found on the amygdala and hippocampus, being the functional abnormalities more consistent and the volumetric changes more inconsistent among studies. From a molecular perspective, CGG repeat size, FMR1 mRNA and FMRP levels have been investigated in relation with the neuroimaging findings. Based on the published results, FMRP might play a key role in the pathophysiology of the psychiatric symptoms described among FMR1 premutation carriers. However, additional studies including further probes of brain function and a broader scope of psychiatric symptom measurement are required in order to obtain a comprehensive landscape of the neuropsychiatric phenotype associated with the FMR1 premutation.

scholarly journals Enhanced detection of expanded repeat mRNA foci with hybridization chain reaction

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
M. Rebecca Glineburg ◽  
Yuan Zhang ◽  
Amy Krans ◽  
Elizabeth M. Tank ◽  
Sami J. Barmada ◽  
...  
Keyword(s):  
Fragile X ◽  
Repeat Expansion ◽  
Nuclear Accumulation ◽  
Hybridization Chain Reaction ◽  
Chain Reaction ◽  
Rna Foci ◽  
Cgg Repeats ◽  
Repeat Expansions ◽  
Ataxia Syndrome

AbstractTranscribed nucleotide repeat expansions form detectable RNA foci in patient cells that contribute to disease pathogenesis. The most widely used method for detecting RNA foci, fluorescence in situ hybridization (FISH), is powerful but can suffer from issues related to signal above background. Here we developed a repeat-specific form of hybridization chain reaction (R-HCR) as an alternative method for detection of repeat RNA foci in two neurodegenerative disorders: C9orf72 associated ALS and frontotemporal dementia (C9 ALS/FTD) and Fragile X-associated tremor/ataxia syndrome. R-HCR to both G4C2 and CGG repeats exhibited comparable specificity but > 40 × sensitivity compared to FISH, with better detection of both nuclear and cytoplasmic foci in human C9 ALS/FTD fibroblasts, patient iPSC derived neurons, and patient brain samples. Using R-HCR, we observed that integrated stress response (ISR) activation significantly increased the number of endogenous G4C2 repeat RNA foci and triggered their selective nuclear accumulation without evidence of stress granule co-localization in patient fibroblasts and patient derived neurons. These data suggest that R-HCR can be a useful tool for tracking the behavior of repeat expansion mRNA in C9 ALS/FTD and other repeat expansion disorders.

scholarly journals Molecular Pathogenesis and Peripheral Monitoring of Adult Fragile X-Associated Syndromes

2021 ◽  
Vol 22 (16) ◽  
pp. 8368
Author(s):  
Luis M. Valor ◽  
Jorge C. Morales ◽  
Irati Hervás-Corpión ◽  
Rosario Marín
Keyword(s):  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Fragile X ◽  
Endocrine System ◽  
Molecular Pathogenesis ◽  
Adult Women ◽  
Adult Men ◽  
Cgg Repeats ◽  
Reproductive Impairment ◽  
Ataxia Syndrome

Abnormal trinucleotide expansions cause rare disorders that compromise quality of life and, in some cases, lifespan. In particular, the expansions of the CGG-repeats stretch at the 5’-UTR of the Fragile X Mental Retardation 1 (FMR1) gene have pleiotropic effects that lead to a variety of Fragile X-associated syndromes: the neurodevelopmental Fragile X syndrome (FXS) in children, the late-onset neurodegenerative disorder Fragile X-associated tremor-ataxia syndrome (FXTAS) that mainly affects adult men, the Fragile X-associated primary ovarian insufficiency (FXPOI) in adult women, and a variety of psychiatric and affective disorders that are under the term of Fragile X-associated neuropsychiatric disorders (FXAND). In this review, we will describe the pathological mechanisms of the adult “gain-of-function” syndromes that are mainly caused by the toxic actions of CGG RNA and FMRpolyG peptide. There have been intensive attempts to identify reliable peripheral biomarkers to assess disease progression and onset of specific pathological traits. Mitochondrial dysfunction, altered miRNA expression, endocrine system failure, and impairment of the GABAergic transmission are some of the affectations that are susceptible to be tracked using peripheral blood for monitoring of the motor, cognitive, psychiatric and reproductive impairment of the CGG-expansion carriers. We provided some illustrative examples from our own cohort. Understanding the association between molecular pathogenesis and biomarkers dynamics will improve effective prognosis and clinical management of CGG-expansion carriers.

CGG repeat length correlates with age of onset of motor signs of the fragile X-associated tremor/ataxia syndrome (FXTAS)

2007 ◽  
Vol 144B (4) ◽  
pp. 566-569 ◽  
Author(s):  
Flora Tassone ◽  
John Adams ◽  
Elizabeth M. Berry-Kravis ◽  
Susannah S. Cohen ◽  
Alfredo Brusco ◽  
...  
Keyword(s):  
Age Of Onset ◽  
Fragile X ◽  
Repeat Length ◽  
Cgg Repeat ◽  
Ataxia Syndrome

scholarly journals CGG repeats in RNA modulate expression of TDP-43 in mouse and fly models of fragile X tremor ataxia syndrome

2014 ◽  
Vol 23 (22) ◽  
pp. 5906-5915 ◽  
Author(s):  
Jocelyn N. Galloway ◽  
Chad Shaw ◽  
Peng Yu ◽  
Deena Parghi ◽  
Mickael Poidevin ◽  
...  
Keyword(s):  
Fragile X ◽  
Cgg Repeats ◽  
Ataxia Syndrome

scholarly journals ASFMR1splice variant

2018 ◽  
Vol 4 (4) ◽  
pp. e246 ◽  
Author(s):  
Padmaja Vittal ◽  
Shrikant Pandya ◽  
Kevin Sharp ◽  
Elizabeth Berry-Kravis ◽  
Lili Zhou ◽  
...  
Keyword(s):  
Mental Retardation ◽  
Splice Variant ◽  
Messenger Rna ◽  
Clinical Symptoms ◽  
Fragile X ◽  
Cgg Repeat ◽  
Men And Women ◽  
Fragile X Mental Retardation ◽  
Repeat Size ◽  
Ataxia Syndrome

ObjectiveTo explore the association of a splice variant of theantisense fragile X mental retardation 1(ASFMR1) gene, loss offragile X mental retardation 1(FMR1) AGG interspersions andFMR1CGG repeat size with manifestation, and severity of clinical symptoms of fragile X-associated tremor/ataxia syndrome (FXTAS).MethodsPremutation carriers (PMCs) with FXTAS, without FXTAS, and normal controls (NCs) had a neurologic evaluation and collection of skin and blood samples. Expression ofASFMR1transcript/splice variant 2 (ASFMR1-TV2), nonsplicedASFMR1, totalASFMR1, andFMR1messenger RNA were quantified and compared using analysis of variance. Least absolute shrinkage and selection operator (LASSO) logistic regression and receiver operating characteristic analyses were performed.ResultsPremutation men and women both with and without FXTAS had higherASFMR1-TV2 levels compared with NC men and women (n = 135,135,p< 0.0001), andASFMR1-TV2 had good discriminating power for FXTAS compared with NCs but not for FXTAS from PMC. After adjusting for age, loss of AGG, larger CGG repeat size (in men), and elevatedASFMR1-TV2 level (in women) were strongly associated with FXTAS compared with NC and PMC (combined).ConclusionsThis study found elevated levels ofASFMR1-TV2and loss of AGG interruptions in both men and women with FXTAS. Future studies will be needed to determine whether these variables can provide useful diagnostic or predictive information.

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