The Known Unknowns: Missing Pieces in in vivo Models of Fragile X Syndrome

Kulkarni, Pushkar; Sevilimedu, Aarti

doi:10.29245/2572-9411/2020/1.1190

Cited by 4 publications

(3 citation statements)

References 36 publications

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“…This, however, comes at the expanse of less powerful genetic tools. The cellular and neurological phenotypes of these KO rats were similar to those of KO mice ( Berzhanskaya et al, 2016 , 2017 ; Kulkarni and Sevilimedu, 2020 ; Tian et al, 2017 ).…”

Section: Introductionmentioning

confidence: 55%

Mouse models of fragile X-related disorders

Willemsen

Kooy

2023

Disease Models &Amp; Mechanisms

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The fragile X-related disorders are an important group of hereditary disorders that are caused by expanded CGG repeats in the 5′ untranslated region of the FMR1 gene or by mutations in the coding sequence of this gene. Two categories of pathological CGG repeats are associated with these disorders, full mutation alleles and shorter premutation alleles. Individuals with full mutation alleles develop fragile X syndrome, which causes autism and intellectual disability, whereas those with premutation alleles, which have shorter CGG expansions, can develop fragile X-associated tremor/ataxia syndrome, a progressive neurodegenerative disease. Thus, fragile X-related disorders can manifest as neurodegenerative or neurodevelopmental disorders, depending on the size of the repeat expansion. Here, we review mouse models of fragile X-related disorders and discuss how they have informed our understanding of neurodegenerative and neurodevelopmental disorders. We also assess the translational value of these models for developing rational targeted therapies for intellectual disability and autism disorders.

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Section: Introductionmentioning

confidence: 55%

Mouse models of fragile X-related disorders

Willemsen

Kooy

2023

Disease Models &Amp; Mechanisms

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“…The topic of sex-dependent differences in symptoms in FXS patients was developed further in preclinical rodent models in rats [110] and mice [21,111,112]. The data obtained via an analysis of Fmr1 KO of both sexes are consistent with the above-described milder phenotype in females compared to affected males [113][114][115][116].…”

Section: Fragile X Syndromementioning

confidence: 72%

Sex Differences in Brain Disorders

Ziemka-Nalecz,

Pawelec,

Ziabska

et al. 2023

IJMS

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A remarkable feature of the brain is its sexual dimorphism. Sexual dimorphism in brain structure and function is associated with clinical implications documented previously in healthy individuals but also in those who suffer from various brain disorders. Sex-based differences concerning some features such as the risk, prevalence, age of onset, and symptomatology have been confirmed in a range of neurological and neuropsychiatric diseases. The mechanisms responsible for the establishment of sex-based differences between men and women are not fully understood. The present paper provides up-to-date data on sex-related dissimilarities observed in brain disorders and highlights the most relevant features that differ between males and females. The topic is very important as the recognition of disparities between the sexes might allow for the identification of therapeutic targets and pharmacological approaches for intractable neurological and neuropsychiatric disorders.

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“…Multiple models for FXS have been generated in flies (Drozd et al, 2018), zebrafish (Vaz et al, 2019), rat (Kulkarni and Sevilimedu, 2020), and mice (Bakker et al, 1994;Mientjes et al, 2006;Dahlhaus, 2018). The mouse model is the most used, as it recapitulates the main phenotype of the disorder.…”

Section: Introductionmentioning

confidence: 99%

Rett Syndrome and Fragile X Syndrome: Different Etiology With Common Molecular Dysfunctions

Bach

Shovlin

Moriarty

et al. 2021

Front. Cell. Neurosci.

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Rett syndrome (RTT) and Fragile X syndrome (FXS) are two monogenetic neurodevelopmental disorders with complex clinical presentations. RTT is caused by mutations in the Methyl-CpG binding protein 2 gene (MECP2) altering the function of its protein product MeCP2. MeCP2 modulates gene expression by binding methylated CpG dinucleotides, and by interacting with transcription factors. FXS is caused by the silencing of the FMR1 gene encoding the Fragile X Mental Retardation Protein (FMRP), a RNA binding protein involved in multiple steps of RNA metabolism, and modulating the translation of thousands of proteins including a large set of synaptic proteins. Despite differences in genetic etiology, there are overlapping features in RTT and FXS, possibly due to interactions between MeCP2 and FMRP, and to the regulation of pathways resulting in dysregulation of common molecular signaling. Furthermore, basic physiological mechanisms are regulated by these proteins and might concur to the pathophysiology of both syndromes. Considering that RTT and FXS are disorders affecting brain development, and that most of the common targets of MeCP2 and FMRP are involved in brain activity, we discuss the mechanisms of synaptic function and plasticity altered in RTT and FXS, and we consider the similarities and the differences between these two disorders.

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The Known Unknowns: Missing Pieces in in vivo Models of Fragile X Syndrome

Cited by 4 publications

References 36 publications

Mouse models of fragile X-related disorders

Mouse models of fragile X-related disorders

Sex Differences in Brain Disorders

Rett Syndrome and Fragile X Syndrome: Different Etiology With Common Molecular Dysfunctions

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