Mouse models for FXTAS and the fragile X premutation

The use of model organisms is essential in order to understand the pathogenesis of many types of human disease, and this is particularly true for the study of genetic diseases such as fragile X syndrome and fragile X-associated tremor/ataxia syndrome (FXTAS). In reverse genetics, the functional study of a gene starts with the question of how a possible phenotype may derive from a specific genetic sequence (disease-causing mutation in a gene). As a first step, a gene function is purposefully altered and the effect on the normal development and/or behavior of the model organism is analyzed. In addition to providing knowledge about the cellular and molecular mechanisms underlying specific genes and their functions, animal models of human disease also provide systems for developing and validating therapeutic strategies. The choice of which animal model is most suitable to mimic a particular disease depends on a range of factors, including anatomical, physiological, and pathological similarity; presence of orthologs of genes of interest; and conservation of basic cell biological and metabolic processes. In this chapter, we will discuss two model organisms, a mammalian vertebrate (mouse) and an invertebrate model (fly), which have been generated to study the pathogenesis of FXTAS and the effects of potential therapeutic interventions. Both mouse and fly models have proven invaluable for the study of the pathophysiology of FXTAS, including insights into the role of mutant mRNA in this disease (i.e., RNA gain-of-function mechanisms, see Chap.

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