p53 is not necessary for DUX4 pathology

Darko Bosnakovski; Erik A. Toso; Olivia O. Recht; Anja Cucak; Abhinav K Jain; Michelle C. Barton; Michael Kyba

Facioscapulohumeral muscular dystrophy (FSHD) affects over 25,000 people in the U.S. alone, making it one of the most prevalent genetic diseases. The genetic mutation underlying FSHD is usually a reduction in the copy number of a macrosatellite repeat on chromosome 4 referred to as D4Z4 (van Deutekom et al. 1993; Wijmenga et al. 1992 ). This repeat is GC-rich, highly methylated, and normally subjected to repeat-induced silencing, which is disrupted in an allelespecific manner by contractions to 10 or fewer copies (van Overveld et al. 2003) or on all D4Z4 repeats by mutation in the chromatin protein SMCHD1 (de Greef et al. 2009; Hartweck et al. 2013 ; Lemmers et al. 2012) . When silencing at D4Z4 breaks down, an RNA transcript encoding the DUX4 protein (Gabriels et al. 1999 ) is expressed. The presence of a poly(A) signal downstream of the D4Z4 repeats on chr4 (Dixit et al. 2007 ) leads to DUX4 expression and explains why disease is associated only with contractions of the D4Z4 repeats on chr4, and only on specific 4qter alleles, so called permissive alleles, which harbor the poly(A) signal (Lemmers et al. 2010; Lemmers et al. 2004 ). The DUX4 protein has been observed by immunostaining of cultured FSHD myoblasts which show infrequent, possibly episodic, expression (Jones et al. 2012; Snider et al. 2010 ) and differentiated myotubes which show more prevalent expression (Block et al. 2013; Rickard, Petek and Miller 2015) .