Facioscapulohumeral muscular dystrophy (FSHD) is a dominant disease linked to 
contractions of the D4Z4 repeat array in 4q35. We have previously identified a 
double homeobox gene (DUX4) within each D4Z4 unit that encodes a transcription 
factor expressed in FSHD but not control myoblasts. DUX4 and its target genes 
contribute to the global dysregulation of gene expression observed in FSHD. We 
have now characterized the homologous DUX4c gene mapped 42 kb centromeric of the 
D4Z4 repeat array. It encodes a 47-kDa protein with a double homeodomain 
identical to DUX4 but divergent in the carboxyl-terminal region. DUX4c was 
detected in primary myoblast extracts by Western blot with a specific antiserum, 
and was induced upon differentiation. The protein was increased about 2-fold in 
FSHD versus control myotubes but reached 2-10-fold induction in FSHD muscle 
biopsies. We have shown by Western blot and by a DNA-binding assay that DUX4c 
over-expression induced the MYF5 myogenic regulator and its DNA-binding 
activity. DUX4c might stabilize the MYF5 protein as we detected their 
interaction by co-immunoprecipitation. In keeping with the known role of Myf5 in 
myoblast accumulation during mouse muscle regeneration DUX4c over-expression 
activated proliferation of human primary myoblasts and inhibited their 
differentiation. Altogether, these results suggested that DUX4c could be 
involved in muscle regeneration and that changes in its expression could 
contribute to the FSHD pathology.