Abstract
Utrophin, the autosomal homologue of dystrophin can functionally compensate for dystrophin deficiency. Utrophin upregulation could therefore be a therapeutic strategy in Duchenne Muscular Dystrophy (DMD) that arises from mutation in dystrophin gene. In contrast to its transcriptional regulation, mechanisms operating at post-transcriptional level of utrophin expression have not been well documented. Although utrophin-A 5'-UTR has been reported with internal ribosome entry site (IRES), its inhibitory effect on translation is also evident. In the present study we therefore aimed to compare relative contribution of cap-independent and cap-dependent translation with mouse utrophin-A 5'-UTR through m7G-capped and A-capped mRNA transfection based reporter assay. Our results demonstrate that cap-independent translation with utrophin-A 5'-UTR is not as strong as viral IRES. However, cap-independent mode has significant contribution as cap-dependent translation is severely repressed with utrophin-A 5'-UTR. We further identified two sequence elements and one upstream open reading frame in utrophin-A 5'-UTR responsible for repression. The repressor elements in utrophin-A 5'-UTR may be targeted for utrophin upregulation.
Highlights
Duchenne Muscular Dystrophy (DMD) is the most frequent genetic disorder which is caused by mutation in X linked dystrophin gene [1, 2]
Recently many authors questioned the existence of internal ribosome entry site (IRES) in cellular mRNAs primarily because of the apparent flaws in the experimental designing
Most of the cellular IRES elements have been reported based on the DNA based dicistronic constructs, where the sequence to be tested was inserted between two reporter cistrons
Summary
Duchenne Muscular Dystrophy (DMD) is the most frequent genetic disorder which is caused by mutation in X linked dystrophin gene [1, 2]. The chromosome 6 encoded utrophin structurally and functionally resembles dystrophin, utrophin expression is reduced postnatally and confined preferentially at neuromuscular and myotendinous junctions in adult mice [3,4,5,6,7]. Overexpression of utrophin in dystrophin deficient mouse muscle fiber either through transgenic experiment or viral vector reduced dystrophic pathology [8,9,10,11]. Utrophin upregulation has been considered as a strategy for functional substitution of defective dystrophin. For an effective therapy of DMD, utrophin expression needs to be upregulated throughout the adult muscle fiber [10, 12,13,14,15,16,17].
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