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01.12.2014 | Review | Ausgabe 1/2014 Open Access

Journal of Neurodevelopmental Disorders 1/2014

Mouse models of the fragile X premutation and fragile X-associated tremor/ataxia syndrome

Zeitschrift:
Journal of Neurodevelopmental Disorders > Ausgabe 1/2014
Autoren:
Robert F Berman, Ronald AM Buijsen, Karen Usdin, Elizabeth Pintado, Frank Kooy, Dalyir Pretto, Isaac N Pessah, David L Nelson, Zachary Zalewski, Nicholas Charlet-Bergeurand, Rob Willemsen, Renate K Hukema
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1866-1955-6-25) contains supplementary material, which is available to authorized users.

Competing interests

DLN patented a method for detecting FMR1 mutation: US PTO 6,107,015 diagnosis of the fragile x syndrome. All other authors declare that they have no competing interests.

Authors’ contributions

All of the authors contributed to the conceptualization and the writing of this review. All authors read and approved the final manuscript.

Abstract

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 Ca2+ 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.
Zusatzmaterial
Authors’ original file for figure 1
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Authors’ original file for figure 2
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Authors’ original file for figure 3
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Authors’ original file for figure 4
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Literatur
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