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

The DUX4 gene encodes several alternative mRNA isoforms generated by alternate 5'splice site usage in the first exon [8] ; however, only the DUX4-full length (DUX4-fl) mRNA is pathogenic when expressed in muscle [8, 15, 19] . DUX4-fl encodes a paired homeobox domain transcription factor (DUX4-FL) normally expressed in healthy human testis, pluripotent cells, and cleavage-stage embryos, and the DUX4-mediated transcriptional program is key for zygotic genome activation, all of which supports an important role for DUX4-FL during early embryonic development [5, 8, [20] [21] [22] [23] . Adult somatic cells from healthy individuals are typically devoid of detectable DUX4-fl expression [8, 15, 16] . However, individuals meeting the genetic criteria for FSHD express stable DUX4-fl mRNA and protein in their skeletal muscles, which aberrantly activates an embryonic gene expression profile [8, 15, 16, 24, 25] , ultimately leading to FSHD pathophysiology. Interestingly, low somatic expression of DUX4-fl mRNA per se is not necessarily pathogenic since expression can be detected in some rare cultures of myogenic cells and muscle biopsies from healthy and asymptomatic FSHD subjects, albeit at levels significantly lower than in equivalent cells and tissues from FSHD-affected subjects [9, 16, 17] . Epigenetic analysis of the pathogenic 4q D4Z4 RU shows that the stability of DUX4 epigenetic repression correlates with disease presentation among healthy, FSHD1-affected, and FSHD1-asymptomatic subjects [9] . Together, this data supports that the level of somatic DUX4-fl expression, which is inducible and affected by the epigenetic stability in the region, is the key determinant of disease onset and severity.