Up71 and Up140, two novel transcripts of utrophin that are homologues of short forms of dystrophin

Utrophin is a large protein which accumulates at the neuromuscular synapse and myotendinous junctions in adult skeletal muscle, and is widely expressed in several non-skeletal muscle tissues. Evidence from a variety of sources suggests that a successful strategy for treatment of Duchenne muscular dystrophy patients will be to increase expression of utrophin in muscle. There is still much to be learnt about utrophin gene regulation, in particular regarding alternative isoforms, their promoters and role in muscle and non-muscle tissues. Using 5'-RACE we have identified two novel transcripts of utrophin, Up71 and Up140, with unique first exons and promoters located in intron 62 and intron 44, respectively. These transcripts appear to be structural homologues of the short dystrophin transcripts, Dp140 and Dp71, emphasizing the high degree of structural conservation between the utrophin and dystrophin genes. RT-PCR shows that Up71 and Up140 are widely expressed in both human and mouse tissues, including skeletal muscle. We present evidence for transcript-specific differential mRNA splicing of exon 71, in both Up71 end Up140, similar to that described for dystrophin. No evidence for splicing of exon 78 of utrophin was found. This is in contrast to dystrophin and may reflect a subtle functional difference in patterns of phosphorylation between the two proteins.