Transgenic mice expressing tunable levels of DUX4 develop characteristic facioscapulohumeral muscular dystrophy-like pathophysiology ranging in severity

Takako I. Jones; Guo-Liang Chew; Pamela Barraza-Flores; Spencer Schreier; Monique Ramirez; Ryan D. Wuebbles; Dean J. Burkin; Robert K. Bradley; Peter L. Jones

Overall, these dose-dependent DUX4-fl FSHD-like phenotypic mouse models strongly support the DUX4 misexpression model for mediating FSHD pathogenesis [15, 18] , and provide a useful and highly flexible tool for performing FSHD preclinical testing of therapeutic approaches targeting DUX4-fl mRNA and protein. Importantly for future analyses, we have shown sex-specific differences, anatomical muscle-specific differences, and model-specific differences that must be taken into account when using these FSHD-like mice. Within a single mouse, one can assess differentially affected muscles. Studying both sexes from a cross provides more fine-tuning of effects as well, with females being slightly but significantly more affected than the males. This provides even greater flexibility and utility for the model as a tool for studying FSHD and testing potential therapeutic approaches.