FMR1 Premutation Allele (CGG)(81) Is Stable in Mice

Bontekoe, Carola; Graaff, Esther de; Nieuwenhuizen, Ingeborg M.; Willemsen, Rob; Oostra, Ben A.

doi:10.1159/000484780

Cited by 45 publications

(35 citation statements)

References 25 publications

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“…However, these transgenic mouse models, both within and outside the context of the FMR1 gene, did not show instability in the trinucleotide repeat length (Bontekoe et al 1997; Lavedan et al 1997, 1998). …”

Section: 2 Mouse Models Of the Fragile X Premutation And Fxtasmentioning

confidence: 93%

Mouse Models of the Fragile X Premutation and the Fragile X Associated Tremor/Ataxia Syndrome

Hunsaker¹,

Arqué²,

Berman³

et al. 2011

Results and Problems in Cell Differentiation

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Carriers of the fragile X premutation (FPM) have CGG trinucleotide repeat expansions of between 55 and 200 in the 5′-UTR of FMR1, compared to a CGG repeat length of between 5 and 54 for the general population. Carriers were once thought to be without symptoms, but it is now recognized that they can develop a variety of early neurological symptoms as well as being at risk for developing the late onset neurodegenerative disorder fragile X-associated tremor/ataxia syndrome (FXTAS). Several mouse models have contributed to our understanding of FPM and FXTAS, and findings from studies using these models are summarized here. This review also discusses how this information is improving our understanding of the molecular and cellular abnormalities that contribute to neurobehavioral features seen in some FPM carriers and in patients with FXTAS. Mouse models show much of the pathology seen in FPM carriers and in individuals with FXTAS, including the presence of elevated levels of Fmr1 mRNA, decreased levels of fragile X mental retardation protein, and ubiquitin-positive intranuclear inclusions. Abnormalities in dendritic spine morphology in several brain regions are associated with neurocognitive deficits in spatial and temporal memory processes, impaired motor performance, and altered anxiety. In vitro studies have identified altered dendritic and synaptic architecture associated with abnormal Ca 2+ dynamics and electrical network activity. FPM mice have been particularly useful in understanding the roles of Fmr1 mRNA, fragile X mental retardation protein, and translation of a potentially toxic polyglycine peptide in pathology. Finally, the potential for using these and emerging mouse models for preclinical development of therapies to improve neurological function in FXTAS is considered.

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Section: 2 Mouse Models Of the Fragile X Premutation And Fxtasmentioning

confidence: 93%

Mouse Models of the Fragile X Premutation and the Fragile X Associated Tremor/Ataxia Syndrome

Hunsaker¹,

Arqué²,

Berman³

et al. 2011

Results and Problems in Cell Differentiation

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“…Transgenic models expressing (CGG) n of lengths that cause instability in humans showed stable transmission to next generations. (80) …”

Section: Cis-acting Factorsmentioning

confidence: 99%

Microsatellite repeat instability and neurological disease

2009

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Over 20 unstable microsatellite repeats have been identified as the cause of neurological disease in humans. The repeat nucleotide sequences, their location within the genes, the ranges of normal and disease-causing repeat length and the clinical outcomes differ. Unstable repeats can be located in the coding or the non-coding region of a gene. Different pathogenic mechanisms that are hypothesised to underlie the diseases are discussed. Evidence is given both from studies in simple model systems and from studies on human material and in animal models. Since somatic instability might affect the clinical outcome, this is briefly touched on. Available data and theories on the timing and mechanisms of the repeat instability itself are discussed, along with factors that have been observed to affect instability. Finally, the question of why the often harmful unstable repeats have been maintained throughout evolution is addressed.

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“…To better understand the timing and mechanism involved in the FMR1 CGG repeat instability and methylation, several attempts to make transgenic mouse models with expanded CGG tracts were undertaken 67 68 69 70. However, since flanking of the expanded CGG repeat with part of the FMR1 gene proved not sufficient to recapitulate all aspects of repeat instability in humans, the endogenous mouse CGG repeat was replaced by a human CGG repeat carrying 98 CGG units 71.…”

Section: Animal Modelsmentioning

confidence: 99%

Fragile X syndrome: from molecular genetics to therapy

D’Hulst

Kooy

2009

Journal of Medical Genetics

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International audienceFragile X syndrome, the main cause of inherited mental retardation, is caused by transcriptional silencing of the , . Absence of the associated protein FMRP leads to the dysregulation of many genes creating a phenotype of ADHD, anxiety, epilepsy and autism. The core aim of this review is to discuss two decades of molecular research leading to the characterisation of cellular and molecular pathways involved in the pathology of this disease and as a consequence to the identification of two new promising targets for rational therapy of fragile X syndrome, namely the group 1 metabotrope glutamate receptors (Gp1 mGluRs) and the gamma-amino butyric acid A receptors (GABA(A)Rs). As no current clinical treatments for fragile x syndrome are directed specifically at the underlying neuronal defect due to absence of FMRP, this might open new powerful therapeutic strategies

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FMR1 Premutation Allele (CGG)(81) Is Stable in Mice

Cited by 45 publications

References 25 publications

Mouse Models of the Fragile X Premutation and the Fragile X Associated Tremor/Ataxia Syndrome

Mouse Models of the Fragile X Premutation and the Fragile X Associated Tremor/Ataxia Syndrome

Microsatellite repeat instability and neurological disease

Fragile X syndrome: from molecular genetics to therapy

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