scholarly journals Isolation and Analysis of the CGG-Repeat Size in Male and Female Gametes from a Fragile X Mouse Model

2019 ◽  
pp. 173-186 ◽  
Author(s):  
Xiaonan Zhao ◽  
Huiyan Lu ◽  
Pradeep K. Dagur ◽  
Karen Usdin
Keyword(s):  
Mouse Model ◽  
Fragile X ◽  
Cgg Repeat ◽  
Male And Female ◽  
Repeat Size

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.

scholarly journals CGG-repeat length and neuropathological and molecular correlates in a mouse model for fragile X-associated tremor/ataxia syndrome

2008 ◽  
Vol 107 (6) ◽  
pp. 1671-1682 ◽  
Author(s):  
Judith R. Brouwer ◽  
Karin Huizer ◽  
Lies-Anne Severijnen ◽  
Renate K. Hukema ◽  
Robert F. Berman ◽  
...  
Keyword(s):  
Mouse Model ◽  
Fragile X ◽  
Repeat Length ◽  
Cgg Repeat ◽  
Ataxia Syndrome

scholarly journals Lack of a Clear Behavioral Phenotype in an Inducible FXTAS Mouse Model Despite the Presence of Neuronal FMRpolyG-Positive Aggregates

2020 ◽  
Vol 7 ◽  
Author(s):  
Saif N. Haify ◽  
Ruchira S. D. Mankoe ◽  
Valerie Boumeester ◽  
Esmay C. van der Toorn ◽  
Rob F. M. Verhagen ◽  
...  
Keyword(s):  
Mouse Model ◽  
Rna Binding ◽  
Neurodegenerative Disorder ◽  
Rna Binding Proteins ◽  
Fragile X ◽  
Brain Regions ◽  
Intranuclear Inclusions ◽  
Behavioral Deficits ◽  
Cgg Repeat ◽  
Progressive Cerebellar Ataxia

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a rare neurodegenerative disorder caused by a 55–200 CGG repeat expansion in the 5′ untranslated region of the Fragile X Mental Retardation 1 (FMR1) gene. FXTAS is characterized by progressive cerebellar ataxia, Parkinsonism, intention tremors and cognitive decline. The main neuropathological hallmark of FXTAS is the presence of ubiquitin-positive intranuclear inclusions in neurons and astrocytes throughout the brain. The molecular pathology of FXTAS involves the presence of 2 to 8-fold elevated levels of FMR1 mRNA, and of a repeat-associated non-AUG (RAN) translated polyglycine peptide (FMRpolyG). Increased levels of FMR1 mRNA containing an expanded CGG repeat can result in cellular toxicity by an RNA gain-of-function mechanism. The increased levels of CGG repeat-expanded FMR1 transcripts may create RNA foci that sequester important cellular proteins, including RNA-binding proteins and FMRpolyG, in intranuclear inclusions. To date, it is unclear whether the FMRpolyG-positive intranuclear inclusions are a cause or a consequence of FXTAS disease pathology. In this report we studied the relation between the presence of neuronal intranuclear inclusions and behavioral deficits using an inducible mouse model for FXTAS. Neuronal intranuclear inclusions were observed 4 weeks after dox-induction. After 12 weeks, high numbers of FMRpolyG-positive intranuclear inclusions could be detected in the hippocampus and striatum, but no clear signs of behavioral deficits related to these specific brain regions were found. In conclusion, the observations in our inducible mouse model for FXTAS suggest a lack of correlation between the presence of intranuclear FMRpolyG-positive aggregates in brain regions and specific behavioral phenotypes.

scholarly journals Repeat Instability in the Fragile X-Related Disorders: Lessons from a Mouse Model

2019 ◽  
Vol 9 (3) ◽  
pp. 52 ◽  
Author(s):  
Xiaonan Zhao ◽  
Inbal Gazy ◽  
Bruce Hayward ◽  
Elizabeth Pintado ◽  
Ye Hwang ◽  
...  
Keyword(s):  
Mouse Model ◽  
Mouse Models ◽  
Molecular Basis ◽  
Fragile X ◽  
Fmr1 Gene ◽  
Repeat Instability ◽  
Cgg Repeat ◽  
Repeat Tract ◽  
Exon 1 ◽  
Clinical Conditions

The fragile X-related disorders (FXDs) are a group of clinical conditions that result primarily from an unusual mutation, the expansion of a CGG-repeat tract in exon 1 of the FMR1 gene. Mouse models are proving useful for understanding many aspects of disease pathology in these disorders. There is also reason to think that such models may be useful for understanding the molecular basis of the unusual mutation responsible for these disorders. This review will discuss what has been learnt to date about mechanisms of repeat instability from a knock-in FXD mouse model and what the implications of these findings may be for humans carrying expansion-prone FMR1 alleles.

scholarly journals Detection of exact fragile X CGG repeat size of embryonic trophectoderm biopsies

2018 ◽  
Vol 110 (4) ◽  
pp. e420
Author(s):  
J.L. Bedard ◽  
C. Jalas ◽  
X. Tao ◽  
R. Scott
Keyword(s):  
Fragile X ◽  
Cgg Repeat ◽  
Repeat Size

scholarly journals Simplified strategy for rapid first-line screening of fragile X syndrome: closed-tube triplet-primed PCR and amplicon melt peak analysis

2015 ◽  
Vol 17 ◽  
Author(s):  
Indhu-Shree Rajan-Babu ◽  
Hai-Yang Law ◽  
Chui-Sheun Yoon ◽  
Caroline G. Lee ◽  
Samuel S. Chong
Keyword(s):  
Fragile X Syndrome ◽  
Large Scale ◽  
Fragile X ◽  
Population Based ◽  
Molecular Diagnostic ◽  
First Line ◽  
Cgg Repeat ◽  
Screening Programs ◽  
Repeat Size ◽  
Closed Tube

Premutation and full-mutation hyperexpansion of CGG-triplets in the X-linkedFragile X Mental Retardation 1(FMR1) gene have been implicated in fragile X-associated tremor/ataxia syndrome, fragile X-associated primary ovarian insufficiency, and fragile X syndrome (FXS), respectively. The currently available molecular diagnostic tests are either costly or labour-intensive, which prohibits their application as a first-lineFMR1test in large-scale population-based screening programs. In this study, we demonstrate the utility of a simplified closed-tube strategy for rapid first-line screening of FXS based on melt peak temperature (Tm) analysis of direct triplet-primed polymerase chain reaction amplicons (dTP-PCR MCA). In addition, we also evaluated the correlation betweenTmand CGG-repeat size based on capillary electrophoresis (CE) of dTP-PCR amplicons. The assays were initially tested on 29FMR1reference DNA samples, followed by a blinded validation on 107 previously characterised patient DNA samples. The dTP-PCR MCA produced distinct melt profiles of higherTmfor samples carrying an expanded allele. Among the samples tested, we also observed a good correlation betweenTmand CGG-repeat size. In the blinded validation study, dTP-PCR MCA accurately classified all normal and expansion carriers, and theFMR1genotypic classification of all samples was completely concordant with the previously determined genotypes as well as the dTP-PCR CE results. This simple and cost-effective MCA-based assay may be useful as a first-line FXS screening tool that could rapidly screen out the large majority of unaffected individuals, thus minimising the number of samples that need to be analysed by Southern blot analysis.

scholarly journals Abnormal AMPAR-mediated synaptic plasticity, cognitive and autistic-like behaviors in a missense Fmr1 mutant mouse model of Fragile X syndrome

2020 ◽  
Author(s):  
Marta Prieto ◽  
Alessandra Folci ◽  
Gwénola Poupon ◽  
Sara Schiavi ◽  
Valeria Buzzelli ◽  
...  
Keyword(s):  
Mouse Model ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Long Term Potentiation ◽  
Surface Expression ◽  
Missense Mutations ◽  
Spine Density ◽  
Cgg Repeat ◽  
Electrophysiological Recordings ◽  
Receptor Surface Expression

AbstractFragile X syndrome (FXS) is the most frequent form of inherited intellectual disability and the best-described monogenic cause of autism. FXS is usually caused by a CGG-repeat expansion in the FMR1 gene leading to its silencing and the loss-of-expression of the Fragile X Mental Retardation Protein (FMRP). Missense mutations were also identified in FXS patients, including the recurrent FMRP-R138Q mutation. To investigate the mechanisms underlying FXS in these patients, we generated a knock-in mouse model (Fmr1R138Q) expressing the FMRP-R138Q protein. We demonstrate that the Fmr1R138Q hippocampus has an increased spine density associated with postsynaptic ultrastructural defects and increased AMPA receptor surface expression. Combining biochemical assays, high-resolution imaging and electrophysiological recordings, we also show that the mutation impairs the hippocampal long-term potentiation (LTP) and leads to socio-cognitive deficits in Fmr1R138Q mice. These findings reveal that the R138Q mutation impacts the synaptic functions of FMRP and highlight potential mechanisms causing FXS in FMRP-R138Q patients.

scholarly journals Refining the risk for fragile X–associated primary ovarian insufficiency (FXPOI) by FMR1 CGG repeat size

2021 ◽  
Author(s):  
Emily Graves Allen ◽  
Krista Charen ◽  
Heather S. Hipp ◽  
Lisa Shubeck ◽  
Ashima Amin ◽  
...  
Keyword(s):  
High Resolution ◽  
Fragile X ◽  
Primary Ovarian Insufficiency ◽  
Ovarian Insufficiency ◽  
Cgg Repeat ◽  
Repeat Size ◽  
Cgg Repeats ◽  
Increased Risk ◽  
Personalized Risk Assessment ◽  
Current Risk

Abstract Purpose Approximately 20–30% of women with an FMR1 premutation experience fragile X–associated primary ovarian insufficiency (FXPOI); however, current risk estimates based on repeat size only identify women with the midrange of repeats to be at the highest risk. Methods To better understand the risk by repeat size, we collected self-reported reproductive histories on 1,668 women and divided them into high-resolution repeat size bins of ~5 CGG repeats to determine a more accurate risk for FXPOI in relation to CGG repeat length. Results As previously reported, women with 70–100 CGG repeats were at the highest risk for FXPOI using various statistical models to compare average age at menopause and risk of FXPOI, with women with 85–89 repeats being at the highest risk. Importantly, women with <65 repeats or >120 repeats did not have a significantly increased risk for FXPOI compared to women with <45 repeats. Conclusion Using a large cross-section study on 1,668 women, we have provided more personalized risk assessment for FXPOI using high-resolution repeat size bins. Understanding the variability in risk has important implications for family planning and overall health among women with a premutation.

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