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Berman RF, Buijsen RA, Usdin K, et al. Mouse models of the fragile X premutation and fragile X-associated tremor/ataxia syndrome. J Neurodev Disord. 2014;6(1):25doi: 10.1186/1866-1955-6-25.
Berman, R. F., Buijsen, R. A., Usdin, K., Pintado, E., Kooy, F., Pretto, D., Pessah, I. N., Nelson, D. L., Zalewski, Z., Charlet-Bergeurand, N., Willemsen, R., & Hukema, R. K. (2014). Mouse models of the fragile X premutation and fragile X-associated tremor/ataxia syndrome. Journal of neurodevelopmental disorders, 6(1), 25. https://doi.org/10.1186/1866-1955-6-25
Berman, Robert F, et al. "Mouse models of the fragile X premutation and fragile X-associated tremor/ataxia syndrome." Journal of neurodevelopmental disorders vol. 6,1 (2014): 25. doi: https://doi.org/10.1186/1866-1955-6-25
Berman RF, Buijsen RA, Usdin K, Pintado E, Kooy F, Pretto D, Pessah IN, Nelson DL, Zalewski Z, Charlet-Bergeurand N, Willemsen R, Hukema RK. Mouse models of the fragile X premutation and fragile X-associated tremor/ataxia syndrome. J Neurodev Disord. 2014;6(1):25. doi: 10.1186/1866-1955-6-25. Epub 2014 Jul 30. PMID: 25136376; PMCID: PMC4135345.
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J Neurodev Disord. 2014;6(1):25. doi: 10.1186/1866-1955-6-25. Epub 2014 Jul 30.

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

Journal of neurodevelopmental disorders

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

Affiliations

  1. Department of Neurological Surgery, Room 502C, UC Davis, 1515 Newton Court, Davis, CA 95618, USA.
  2. Department Clinical Genetics, Erasmus MC, Rotterdam, Netherlands.
  3. NIDDK, National Institutes of Health, Bethesda, MD, USA.
  4. University of Seville, School of Medicine, Seville, Spain.
  5. Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
  6. UC Davis M.I.N.D. Institute, Sacramento, CA, USA.
  7. Department Molecular Biosciences, UC Davis, Davis, CA, USA.
  8. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
  9. Department of Translational Medicine, IGBMC, Illkirch, France.

PMID: 25136376 PMCID: PMC4135345 DOI: 10.1186/1866-1955-6-25

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 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.

Keywords: CGG trinucleotide repeat; FMR1; FMRP; FXTAS; Fragile X premutation; Intranuclear inclusions; Mouse models; RNA toxicity

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