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 caused by the absence of a muscle cytoskeletal protein, dystrophin. We have previously shown that utrophin, the autosomal homologue of dystrophin, is able to compensate for the absence of dystrophin in a mouse model of DMD; we have therefore undertaken a detailed study of the transcriptional regulation of utrophin to identify means of effecting its up-regulation in DMD muscle. We have previously isolated a promoter element lying within the CpG island 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 lying 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 expressed unique first exon that splices into a common full-length mRNA at exon 3. The two utrophin promoters are independently regulated, and we predict that they respond to discrete sets of cellular signals. These findings significantly contribute to understanding the molecular physiology of utrophin expression 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, therefore, be a more suitable target for pharmacological manipulation than the previously described promoter.
Burton
E A
EA
Department of Human Anatomy, University of Oxford, South Parks Road, Oxford OX1 3QX, United Kingdom.
Tinsley
J M
JM
Holzfeind
P J
PJ
Rodrigues
N R
NR
Davies
K E
KE
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002874:Chromosome Mapping; D003001:Cloning, Molecular; D003598:Cytoskeletal Proteins / Q000235:genetics*; D005091:Exons; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger; D012689:Sequence Homology, Nucleic Acid; D015854:Up-Regulation; D049411:Utrophin
D003598:Cytoskeletal Proteins; D008565:Membrane Proteins; D012333:RNA, Messenger; C483600:Utrn protein, mouse; D049411:Utrophin