Facioscapulohumeral muscular dystrophy (FSHD) is a common form of muscular 
dystrophy characterized by an asymmetric progressive weakness and wasting of the 
facial, shoulder and upper arm muscles, frequently accompanied by hearing loss 
and retinal vasculopathy. FSHD is an autosomal dominant disease linked to 
chromosome 4q35, but the causative gene remains controversial. DUX4 is a leading 
candidate gene as causative of FSHD. However, DUX4 expression is extremely low 
in FSHD muscle, and there is no DUX4 animal model that mirrors the pathology in 
human FSHD. Here, we show that the misexpression of very low levels of human 
DUX4 in zebrafish development recapitulates the phenotypes seen in human FSHD 
patients. Microinjection of small amounts of human full-length DUX4 (DUX4-fl) 
mRNA into fertilized zebrafish eggs caused asymmetric abnormalities such as less 
pigmentation of the eyes, altered morphology of ears, developmental abnormality 
of fin muscle, disorganization of facial musculature and/or degeneration of 
trunk muscle later in development. Moreover, DUX4-fl expression caused aberrant 
localization of myogenic cells marked with α-actin promoter-driven enhanced 
green fluorescent protein outside somite boundary, especially in head region. 
These abnormalities were rescued by coinjection of the short form of DUX4 
(DUX4-s). Our results suggest that the misexpression of DUX4-fl, even at 
extremely low level, can recapitulate the phenotype observed in FSHD patients in 
a vertebrate model. These results strongly support the current hypothesis for a 
role of DUX4 in FSHD pathogenesis. We also propose that DUX4 expression during 
development is important for the pathogenesis of FSHD.