Alternative utrophin mRNAs contribute to phenotypic differences between dystrophin-deficient mice and Duchenne muscular dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is a fatal disorder caused by absence of functional dystrophin protein. Compensation in dystrophin-deficient (mdx) mice may be achieved by overexpression of its fetal paralogue, utrophin. Strategies to increase utrophin levels by stimulating promoter activity using small compounds are therefore a promising pharmacological approach. Here, we characterise similarities and differences existing within the mouse and human utrophin locus to assist in high-throughput screening for potential utrophin modulator drugs. We identified five novel 5'-utrophin isoforms (A',B',C,D and F) in adult and embryonic tissue. As the more efficient utrophin-based response in mdx skeletal muscle appears to involve independent transcriptional activation of conserved, myogenic isoforms (A' and F), elevating their paralogues in DMD patients is an encouraging therapeutic strategy.

Keywords: Duchenne muscular dystrophy; therapy; utrophin.