P.16.2 The DUX4 promoter is expressed in FSHD-affected tissues

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disorder with a 1 in 7500 incidence. Symptoms typically arise in young adulthood and most patients show clinical features before age 30. FSHD is most commonly characterized by progressive wasting and weakness of facial and shoulder-girdle muscles, although no consistent pattern of penetrance or severity exists, even within affected families. A hallmark characteristic of FSHD is asymmetrical muscle weakness. There are also non-muscular features including retinal vasculopathy and high frequency hearing loss. Several recent breakthroughs now support a model in which mis-expression of the myotoxic DUX4 gene is a primary pathogenic event underlying FSHD. We hypothesized that there was a direct correlation between DUX4 expression patterns and the involvement of selected muscles (and ear and retinal pathologies) in FSHD. In short, we proposed that if DUX4 over-expression is indeed an underlying pathogenic event in FSHD, it must be preferentially expressed in FSHD-affected regions. To test this hypothesis, we developed transgenic reporter mice containing a putative DUX4 promoter cloned upstream of GFP. We generated three separate lines of DUX4 promoter-GFP mice. We found the DUX4 promoter directed GFP expression in the face and limbs of newborn and adult mice, as well as multiple cell types in the retina. Essentially all other organs were GFP negative with a few exceptions including the pancreas and brain (cerebellum, olfactory bulb, and hippocampus). Strikingly, all lines showed asymmetrical expression and variable penetrance in all GFP-positive tissues, even within individual litters. We conclude that our mice faithfully recapitulate expected DUX4 expression patterns in regions of FSHD pathology, and further suggest the role of DUX4 as pathogenic insult in FSHD. We are now using a modified but analogous system to inducibly express DUX4.