OVEREXPRESSION OF 3'-UNTRANSLATED REGION OF THE MYOTONIC-DYSTROPHY KINASE CDNA INHIBITS MYOBLAST DIFFERENTIATION IN-VITRO

The genetic defect underlying myotonic dystrophy (DM) has been identif ied as an unstable CTG trinucleotide repeat amplification in the 3'-un translated region (3'-UTR) of the DM kinase gene (DMK). Individuals wi th the most severe congenital form display a marked delay in muscle te rminal differentiation. To gain insight into the role of DMK during my ogenesis, we have examined the effect of DMK overexpression on the ter minal differentiation of the murine myoblast cell line C2C12, We demon strate that a 4-10-fold constitutive overexpression of DMK mRNA in myo blasts caused a marked inhibition of terminal differentiation. Surpris ingly, this activity was mapped to a 239-nucleotide region of the 3'-U TR of the DMK transcript. When the DMK 3'-UTR was placed downstream of a reporter gene, the same inhibition of myogenesis was observed, Foll owing the induction of differentiation of myoblast clones overexpressi ng the DMK 3'-UTR, the levels of myogenin mRNA were reduced by approxi mately Li-fold, whereas the steady state levels of mef-2c transcripts were not affected. These data suggest that overexpression of the DMK 3 '-UTR may interfere with the expression of muscle leading to a delay i n terminal specific mRNAs differentiation.