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Title: Transcription of the utrophin gene : identification and characterisation of novel transcripts
Author: Wilson, James Baillie
ISNI:       0000 0001 3570 2764
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2000
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Utrophin is a large protein, which accummulates at the neuromuscular and myotendinous junctions in the adult skeletal muscle, and is widely expressed in several non-muscle tissues. Evidence from a variety of sources suggests that a successful strategy for treatment of Duchenne muscular dystrophy will be to increase the expression of utrophin in muscle. In order to facilitate this much needs to be learnt about utrophin gene regulation, in particular about alternative isoforms, their promoters and their role in muscle and non-muscle tissues. My project involved searching for novel transcripts transcribed from the utrophin gene. Two novel transcripts of utrophin, Up71 and Up140, with unique first exons and promoters located in intron 62 and intron 44, respectively have been identified in mRNA from brain by 5' RACE. 5' RACE using primers designed to amplify forms of the full-length utrophin failed to find alternative full-length forms in the brain or lung. The expression pattern for Up140 and Up71 was investigated using RT-PCR and Western blotting, which revealed that both Up140 and Up71 mRNA are expressed in a wide variety of both human and mouse tissues, including skeletal muscle. However there was little evidence that this mRNA was translated widely. However a novel 120 kDa polypeptide was specifically detected in kidney. Further characterisation of Up140 and Up71 mRNA revealed that they show transcript-specific differential splicing of exon 71 similar to that described for dystrophin isoforms. However no evidence for splicing of exon 78 of the utrophin gene was found, which was in contrast to dystrophin and may reflect subtle differences in the pattern of phosphorylation between the two proteins. Genomic sequences corresponding to Up71 and Up140 were isolated and the sequence of their proximal promoters explored. The possible functions for the short utrophin transcripts are described and their evolutionary significance explored.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available