Objective: To describe the development of mouse models of fragile Xassociated tremor/ataxia (FXTAS) and the behavioral, histological and molecular characteristics of these mice. Method: This paper compares the pathophysiology and neuropsychological features of FXTAS in humans to the major mouse models of FXTAS. Specifically, the development of a transgenic mouse line carrying an expanded CGG trinucleotide repeat in the 5'-untranslated region (5'-UTR) of the Fmr1 gene is described along with a description of the characteristic intranuclear ubiquitin-positive inclusions and the behavioral sequella observed in these mice. Results: CGG KI mice model many of the important features of FXTAS, although some aspects are not well modeled in mice. Aspects of FXTAS that are modeled well include elevated levels of Fmr1 mRNA, reduced levels of Fmrp, the presence of intranuclear inclusions that develop with age and show similar distributions within neurons, and neuropsychological and cognitive deficits, including poor motor function, impaired memory and evidence of increased anxiety. Features of FXTAS that are not well modeled in these mice include intentional tremors that are observed in some FXTAS patients but have not been reported in CGG KI mice. In addition, although intranuclear inclusions in astrocytes are very prominent in FXTAS, there are relatively few observed in CGG KI mice. A number of additional features of FXTAS have not been systematically examined in mouse models yet, including white matter disease, hyperintensities in T2-weighted magnetic resonance imaging, and brain atrophy, although these are currently under investigation in our laboratories. Conclusions: The available mouse model has provided valuable insights into the molecular biology and pathophysiology of FXTAS and will be particularly useful for developing and testing new therapeutic treatments in the future.

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doi.org/10.231/JIM.0b013e3181af59d6, hdl.handle.net/1765/64050
Journal of Investigative Medicine
Department of Clinical Genetics

Berman, R., & Willemsen, R. (2009). Mouse models of fragile X-associated tremor ataxia. In Journal of Investigative Medicine (Vol. 57, pp. 837–841). doi:10.231/JIM.0b013e3181af59d6