title: A- and B-utrophin have different expression patterns and are differentially up-regulated in mdx muscle.
abstract: Duchenne muscular dystrophy (DMD) is a fatal childhood disease caused by mutations that abolish the expression of dystrophin in muscle. Utrophin is a paralogue of dystrophin and can functionally replace it in skeletal muscle. A method to induce utrophin up-regulation in muscle should therefore be therapeutically useful in DMD. We have previously shown that there are two full-length utrophin mRNA species: A and B. Here we describe the generation and characterization of antibodies specific to A- and B-utrophin. We show that both mRNA isoforms are translated into full-length proteins, which have very different expression patterns. B-utrophin is expressed in vascular endothelial cells; A-utrophin is expressed at the neuromuscular junction, choroid plexus, pia mater, and renal glomerulus. We have analyzed the expression of A- and B-utrophin protein and RNA in dystrophin-deficient tissues. We conclude that (i) the previously described expression patterns of utrophin represent a composite of A- and B-utrophin, (ii) A- but not B-utrophin is up-regulated in dystrophin-deficient striated muscle, and (iii) this up-regulation occurs post-transcriptionally with an additional transcriptional component in skeletal muscle. These results have important implications for understanding the biology of utrophin and are crucial for future studies aiming to effect its therapeutic up-regulation in DMD patients.
authors.affiliation: Medical Research Council Functional Genetics Unit, Department of Human Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, United Kingdom.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Weir
authors.forename: Edward A
authors.initials: EA
authors.lastname: Burton
authors.forename: Graham
authors.initials: G
authors.lastname: Harrod
authors.forename: Kay E
authors.initials: KE
authors.lastname: Davies
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000166:cytology / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D000939:Epitopes; D006801:Humans; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism / Q000503:physiopathology*; D020388:Muscular Dystrophy, Duchenne / Q000378:metabolism* / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D014018:Tissue Distribution; D015854:Up-Regulation / Q000502:physiology*; D049411:Utrophin
chemical_list: D003598:Cytoskeletal Proteins; D000939:Epitopes; D008565:Membrane Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; C483600:Utrn protein, mouse; D049411:Utrophin