G.P.110 The DUX4 promoter is preferentially expressed in FSHD-affected tissues

Abstract

Abstract Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disorder with a one 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. The hallmark characteristic of FSHD is asymmetrical muscle weakness. There are also non-muscular features including retinal vasculopathy and high frequency hearing loss. The pathogenic mechanisms underlying FSHD have been difficult to discern, and scientists in the field have spent most of the last two decades attempting to decipher FSHD pathogenesis. Several recent breakthroughs now support a model in which mis-expression of the myotoxic DUX4 gene is a primary pathogenic event underlying FSHD. We recently showed that DUX4 is generally toxic to muscles, and we therefore hypothesized that there was a direct correlation between DUX4 expression patterns and the involvement of only selected muscles (and ear and retinal pathologies) in FSHD. In short, we proposed that if DUX4 over-expression is indeed the 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 the retina and inner ear. Essentially all other organs were GFP negative. Strikingly, all lines showed asymmetrical expression and variable penetrance, even within individual litters. We conclude that our mice faithfully recapitulate expected DUX4 expression patterns in regions of FSHD pathology, and further support the role of DUX4 as pathogenic insult in FSHD.