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 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 Secondary Structure and Dynamics of the r(CGG) Repeat in the mRNA of the Fragile X Mental Retardation 1(FMR1)Gene

RNA Biology ◽  
2007 ◽  
Vol 4 (2) ◽  
pp. 93-100 ◽  
Author(s):  
Marta Zumwalt ◽  
Anna Ludwig ◽  
Paul J. Hagerman ◽  
Thorsten Dieckmann
Keyword(s):  
Mental Retardation ◽  
Secondary Structure ◽  
Fragile X ◽  
Fmr1 Gene ◽  
Cgg Repeat ◽  
Fragile X Mental Retardation ◽  
Structure And Dynamics

scholarly journals Screening for FMR1 CGG Repeat Expansion in Thai Patients with Autism Spectrum Disorder

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Areerat Hnoonual ◽  
Charunee Jankittunpaiboon ◽  
Pornprot Limprasert
Keyword(s):  
Autism Spectrum Disorder ◽  
Fragile X ◽  
Single Gene ◽  
Autism Spectrum ◽  
Spectrum Disorder ◽  
Fmr1 Gene ◽  
Normal Male ◽  
Cgg Repeat ◽  
Cgg Repeats ◽  
Normal Controls

Autism spectrum disorder (ASD) is a complex disorder with a heterogeneous etiology. Fragile X syndrome (FXS) is recognized as the most common single gene mutation associated with ASD. FXS patients show some autistic behaviors and may be difficult to distinguish at a young age from autistic children. However, there have been no published reports on the prevalence of FXS in ASD patients in Thailand. In this study, we present a pilot study to analyze the CGG repeat sizes of the FMR1 gene in Thai autistic patients. We screened 202 unrelated Thai patients (168 males and 34 females) with nonsyndromic ASD and 212 normal controls using standard FXS molecular diagnosis techniques. The distributions of FMR1 CGG repeat sizes in the ASD and normal control groups were similar, with the two most common alleles having 29 and 30 CGG repeats, followed by an allele with 36 CGG repeats. No FMR1 full mutations or premutations were found in either ASD individuals or the normal controls. Interestingly, three ASD male patients with high normal CGG and intermediate CGG repeats (44, 46, and 53 CGG repeats) were identified, indicating that the prevalence of FMR1 intermediate alleles in Thai ASD patients was approximately 1% while these alleles were absent in the normal male controls. Our study indicates that CGG repeat expansions of the FMR1 gene may not be a common genetic cause of nonsyndromic ASD in Thai patients. However, further studies for mutations other than the CGG expansion in the FMR1 gene are required to get a better information on FXS prevalence in Thai ASD patients.

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 Expanded alleles of the FMR1 gene are related to unexplained recurrent miscarriages

2017 ◽  
Vol 37 (6) ◽  
Author(s):  
Xin-hua Wang ◽  
Xiao-hua Song ◽  
Yan-lin Wang ◽  
Xing-hua Diao ◽  
Tong Li ◽  
...  
Keyword(s):  
Recurrent Miscarriage ◽  
Fragile X ◽  
Fmr1 Gene ◽  
Case Group ◽  
Cgg Repeat ◽  
Recurrent Miscarriages ◽  
Future Studies ◽  
Expanded Allele ◽  
The Impact ◽  
Control Study

Up to 50% of recurrent miscarriage cases in women occur without an underlying etiology. In the current prospective case–control study, we determined the impact of CGG trinucleotide expansions of the fragile-X mental retardation 1 (FMR1) gene in 49 women with unexplained recurrent miscarriages. Case group consisted of women with two or more unexplained consecutive miscarriages. Blood samples were obtained and checked for the presence of expanded alleles of the FMR1 gene using PCR. Patients harboring the expanded allele, with a threshold set to 40 repeats, were further evaluated by sequencing. The number of abortions each woman had, was not associated with her respective CGG repeat number (P=0.255). The repeat sizes of CGG expansion in the FMR1 gene were significantly different in the two population groups (P=0.027). All the positive cases involved intermediate zone carriers. Hence, the CGG expanded allele of the FMR1 gene might be associated with unexplained multiple miscarriages; whether such an association is coincidental or causal can be confirmed by future studies using a larger patient cohort.

scholarly journals Neurocognitive endophenotypes in CGG KI and Fmr1 KO mouse models of Fragile X-Associated disorders: an analysis of the state of the field

F1000Research ◽  
2013 ◽  
Vol 2 ◽  
pp. 287 ◽  
Author(s):  
Michael R. Hunsaker
Keyword(s):  
Mouse Model ◽  
Mouse Models ◽  
Trinucleotide Repeat ◽  
Fragile X ◽  
Treatment Strategies ◽  
Preliminary Evidence ◽  
Future Research ◽  
Behavioral Experiments ◽  
Knock Out ◽  
Fragile X Premutation

It has become increasingly important that the field of behavioral genetics identifies not only the gross behavioral phenotypes associated with a given mutation, but also the behavioral endophenotypes that scale with the dosage of the particular mutation being studied. Over the past few years, studies evaluating the effects of the polymorphic CGG trinucleotide repeat on theFMR1gene underlying Fragile X-Associated Disorders have reported preliminary evidence for a behavioral endophenotype in human Fragile X Premutation carrier populations as well as the CGG knock-in (KI) mouse model. More recently, the behavioral experiments used to test the CGG KI mouse model have been extended to theFmr1knock-out (KO) mouse model. When combined, these data provide compelling evidence for a clear neurocognitive endophenotype in the mouse models of Fragile X-Associated Disorders such that behavioral deficits scale predictably with genetic dosage. Similarly, it appears that the CGG KI mouse effectively models the histopathology in Fragile X-Associated Disorders across CGG repeats well into the full mutation range, resulting in a reliable histopathological endophenotype. These endophenotypes may influence future research directions into treatment strategies for not only Fragile X Syndrome, but also the Fragile X Premutation and Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS).

Abnormal neurogensis in the hippocampus of a mouse model of fragile X syndromes

2007 ◽  
Vol 30 (4) ◽  
pp. 80
Author(s):  
B Eadie ◽  
B Christie
Keyword(s):  
Mouse Model ◽  
Learning And Memory ◽  
Fragile X Syndrome ◽  
Knockout Mice ◽  
Fragile X ◽  
Single Gene ◽  
Neurodevelopmental Disorder ◽  
Autism Spectrum ◽  
Fmr1 Gene ◽  
Learning Impairment

Fragile X syndrome is the most common inherited form of mental retardation. It is a neurodevelopmental disorder that is similar in clinical presentation to autism spectrum disorder. However, unlike autism, Fragile X syndrome is caused by the silencing of a single gene, and in recent years, a mouse model of Fragile X syndrome has been generated by deletion of the Fmr1 gene. Surprisingly, a clear neurobiological basis for the learning impairment observed in both these knockout mice and patients has been difficult to elucidate. We hypothesized that neurogenesis, a process that continues into adulthood in the hippocampus, may be abnormal in this syndrome. Support for such a hypothesis comes from the findings that these new neurons may disproportionately contribute to synaptic plasticity in networks engaged during learning and memory. We have shown that the survival of new cells in the hippocampus of young Fmr1 knockout mice is significantly decreased in the ventral hippocampus, a sub-region which may be more involved with emotional, rather than, spatial memory. Further experiments are being conducted to assess the differentiation of these new cells into neurons and glia. We are also characterizing the normal expression of the Fmr1 gene product, FMRP, across the phases of neurogenesis in control mice. In conclusion, we have discovered a clear impairment in a process that may be critical to emotionally-significant learning and memory in a mouse model of Fragile X syndrome.

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