A second promoter provides an alternative target for therapeutic up-regulation of utrophin in Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is an inherited muscle-wasting disease ca used by the absence of a muscle cytoskeletal protein, dystrophin. We have p reviously shown that utrophin, the autosomal homologue of dystrophin, is ab le to compensate for the absence of dystrophin in a mouse model of DMD; we have therefore undertaken a detailed study of the transcriptional regulatio n of utrophin to identify means of effecting its up-regulation in DMD muscl e. We have previously isolated a promoter element lying within the CpG isla nd at the 5' end of the gene and have shown it to be synaptically regulated in vivo. In this paper, we show that there is an alternative promoter lyin g within the large second intron of the utrophin gene, 50 kb 3' to exon 2. The promoter is highly regulated and drives transcription of a widely expre ssed unique first exon that splices into a common full-length mRNA at exon 3. The two utrophin promoters are independently regulated, and we predict t hat they respond to discrete sets of cellular signals. These findings signi ficantly contribute to understanding the molecular physiology of utrophin e xpression and are important because the promoter reported here provides an alternative target for transcriptional activation of utrophin in DMD muscle . This promoter does not contain synaptic regulatory elements and might, th erefore, be a more suitable target for pharmacological manipulation than th e previously described promoter.