Mouse models of the fragile X premutation and fragile X-associated tremor/ataxia syndrome / Robert F. BERMAN in Journal of Neurodevelopmental Disorders, 6-1 (December 2014)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 6-1 (December 2014) . - p.25 Titre : Mouse models of the fragile X premutation and fragile X-associated tremor/ataxia syndrome Type de document : Texte imprimé et/ou numérique Auteurs : Robert F. BERMAN, Auteur ; R. A. BUIJSEN, Auteur ; K. USDIN, Auteur ; E. PINTADO, Auteur ; F. KOOY, Auteur ; D. PRETTO, Auteur ; I. N. PESSAH, Auteur ; D. L. NELSON, Auteur ; Z. ZALEWSKI, Auteur ; N. CHARLET-BERGEURAND, Auteur ; R. WILLEMSEN, Auteur ; R. K. HUKEMA, Auteur Article en page(s) : p.25 Langues : Anglais (eng) Mots-clés : CGG trinucleotide repeat  Fmr1  Fmrp  Fxtas  Fragile X premutation  Intranuclear inclusions  Mouse models  RNA toxicity Index. décimale : PER Périodiques Résumé : 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. En ligne : http://dx.doi.org/10.1186/1866-1955-6-25 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=346 [article] Mouse models of the fragile X premutation and fragile X-associated tremor/ataxia syndrome [Texte imprimé et/ou numérique] / Robert F. BERMAN, Auteur ; R. A. BUIJSEN, Auteur ; K. USDIN, Auteur ; E. PINTADO, Auteur ; F. KOOY, Auteur ; D. PRETTO, Auteur ; I. N. PESSAH, Auteur ; D. L. NELSON, Auteur ; Z. ZALEWSKI, Auteur ; N. CHARLET-BERGEURAND, Auteur ; R. WILLEMSEN, Auteur ; R. K. HUKEMA, Auteur . - p.25. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 6-1 (December 2014) . - p.25 Mots-clés : CGG trinucleotide repeat  Fmr1  Fmrp  Fxtas  Fragile X premutation  Intranuclear inclusions  Mouse models  RNA toxicity Index. décimale : PER Périodiques Résumé : 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. En ligne : http://dx.doi.org/10.1186/1866-1955-6-25 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=346

Use of model systems to understand the etiology of fragile X-associated primary ovarian insufficiency (FXPOI) / S. L. SHERMAN in Journal of Neurodevelopmental Disorders, 6-1 (December 2014)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 6-1 (December 2014) . - p.26 Titre : Use of model systems to understand the etiology of fragile X-associated primary ovarian insufficiency (FXPOI) Type de document : Texte imprimé et/ou numérique Auteurs : S. L. SHERMAN, Auteur ; E. C. CURNOW, Auteur ; C. A. EASLEY, Auteur ; P. JIN, Auteur ; R. K. HUKEMA, Auteur ; M. I. TEJADA, Auteur ; R. WILLEMSEN, Auteur ; K. USDIN, Auteur Article en page(s) : p.26 Langues : Anglais (eng) Mots-clés : CGG repeat  Fertility  Fragile X syndrome  Premature ovarian failure  Primary ovarian insufficiency  Repeat expansion disorder Index. décimale : PER Périodiques Résumé : Fragile X-associated primary ovarian insufficiency (FXPOI) is among the family of disorders caused by the expansion of a CGG repeat sequence in the 5' untranslated region of the X-linked gene FMR1. About 20% of women who carry the premutation allele (55 to 200 unmethylated CGG repeats) develop hypergonadotropic hypogonadism and cease menstruating before age 40. Some proportion of those who are still cycling show hormonal profiles indicative of ovarian dysfunction. FXPOI leads to subfertility and an increased risk of medical conditions associated with early estrogen deficiency. Little progress has been made in understanding the etiology of this clinically significant disorder. Understanding the molecular mechanisms of FXPOI requires a detailed knowledge of ovarian FMR1 mRNA and FMRP's function. In humans, non-invasive methods to discriminate the mechanisms of the premutation on ovarian function are not available, thus necessitating the development of model systems. Vertebrate (mouse and rat) and invertebrate (Drosophila melanogaster) animal studies for the FMR1 premutation and ovarian function exist and have been instrumental in advancing our understanding of the disease phenotype. For example, rodent models have shown that FMRP is highly expressed in oocytes where it is important for folliculogenesis. The two premutation mouse models studied to date show evidence of ovarian dysfunction and, together, suggest that the long repeat in the transcript itself may have some pathological effect quite apart from any effect of the toxic protein. Further, ovarian morphology in young animals appears normal and the primordial follicle pool size does not differ from that of wild-type animals. However, there is a progressive premature decline in the levels of most follicle classes. Observations also include granulosa cell abnormalities and altered gene expression patterns. Further comparisons of these models are now needed to gain insight into the etiology of the ovarian dysfunction. Premutation model systems in non-human primates and those based on induced pluripotent stem cells show particular promise and will complement current models. Here, we review the characterization of the current models and describe the development and potential of the new models. Finally, we will discuss some of the molecular mechanisms that might be responsible for FXPOI. En ligne : http://dx.doi.org/10.1186/1866-1955-6-26 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=346 [article] Use of model systems to understand the etiology of fragile X-associated primary ovarian insufficiency (FXPOI) [Texte imprimé et/ou numérique] / S. L. SHERMAN, Auteur ; E. C. CURNOW, Auteur ; C. A. EASLEY, Auteur ; P. JIN, Auteur ; R. K. HUKEMA, Auteur ; M. I. TEJADA, Auteur ; R. WILLEMSEN, Auteur ; K. USDIN, Auteur . - p.26. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 6-1 (December 2014) . - p.26 Mots-clés : CGG repeat  Fertility  Fragile X syndrome  Premature ovarian failure  Primary ovarian insufficiency  Repeat expansion disorder Index. décimale : PER Périodiques Résumé : Fragile X-associated primary ovarian insufficiency (FXPOI) is among the family of disorders caused by the expansion of a CGG repeat sequence in the 5' untranslated region of the X-linked gene FMR1. About 20% of women who carry the premutation allele (55 to 200 unmethylated CGG repeats) develop hypergonadotropic hypogonadism and cease menstruating before age 40. Some proportion of those who are still cycling show hormonal profiles indicative of ovarian dysfunction. FXPOI leads to subfertility and an increased risk of medical conditions associated with early estrogen deficiency. Little progress has been made in understanding the etiology of this clinically significant disorder. Understanding the molecular mechanisms of FXPOI requires a detailed knowledge of ovarian FMR1 mRNA and FMRP's function. In humans, non-invasive methods to discriminate the mechanisms of the premutation on ovarian function are not available, thus necessitating the development of model systems. Vertebrate (mouse and rat) and invertebrate (Drosophila melanogaster) animal studies for the FMR1 premutation and ovarian function exist and have been instrumental in advancing our understanding of the disease phenotype. For example, rodent models have shown that FMRP is highly expressed in oocytes where it is important for folliculogenesis. The two premutation mouse models studied to date show evidence of ovarian dysfunction and, together, suggest that the long repeat in the transcript itself may have some pathological effect quite apart from any effect of the toxic protein. Further, ovarian morphology in young animals appears normal and the primordial follicle pool size does not differ from that of wild-type animals. However, there is a progressive premature decline in the levels of most follicle classes. Observations also include granulosa cell abnormalities and altered gene expression patterns. Further comparisons of these models are now needed to gain insight into the etiology of the ovarian dysfunction. Premutation model systems in non-human primates and those based on induced pluripotent stem cells show particular promise and will complement current models. Here, we review the characterization of the current models and describe the development and potential of the new models. Finally, we will discuss some of the molecular mechanisms that might be responsible for FXPOI. En ligne : http://dx.doi.org/10.1186/1866-1955-6-26 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=346

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