Sticky utrophin messages

杨柳

On page 1173, Gramolini et al. report that utrophin mRNA is immobilized by binding to an actin-dependent structure. Manipulation of this system may be important for the therapy of Duchenne muscular dystrophy (DMD).1 T& S" u4 ~9 D6 y3 u

, H) q% A) k# _) \4 ADMD is characterized by a weakened linkage from muscle cells to the extracellular matrix because of a compromised dystrophin complex. Utrophin may be able to substitute for dystrophin, but utrophin's expression is normally limited to the areas near where nerves contact muscle cells. This is due, at least in part, to the concentration of utrophin mRNA to these regions.
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In multinucleated muscle cells, the utrophin gene is preferentially expressed from nuclei that are close to the sites of nerve contact. Gramolini et al. now find that this high localized concentration of mRNA is then maintained by the binding of utrophin polysomes, via the utrophin 3' untranslated region, to actin-dependent structures.
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) d5 i  C8 o) V1 V( ]The possible relevance of these results to DMD therapy arises because individuals with DMD may mount an immune response to dystrophin introduced by gene therapy, given that the individual's body has never seen the protein before. Although increased expression of utrophin should not cause such an autoimmune reaction, the localization of utrophin translation may limit utrophin's usefulness. If, however, the tethering system described by Gramolini et al. can be manipulated with small molecules, the dispersed expression of utrophin may act as one element of a DMD therapy.(Utrophin mRNAs bind to actin.)