DISRUPTION OF SPLICING REGULATED BY A CUG-BINDING PROTEIN IN MYOTONIC-DYSTROPHY

Myotonic dystrophy (DM) is caused by a CTG expansion in the 3' untrans lated region of the DM gene. One model of DM pathogenesis suggests tha t RNAs from the expanded allele create a gain-of-function mutation by the inappropriate binding of proteins to the CUG repeats. Data present ed here indicate that the conserved heterogeneous nuclear ribonucleopr otein, CUG-binding protein (CUG-BP), may mediate the trans-dominant ef fect of the RNA. CUG-BP was found to bind to the human cardiac troponi n T (cTNT) pre-messenger RNA and regulate its alternative splicing. Sp licing of cTNT was disrupted in DM striated muscle and in normal cells expressing transcripts that contain CUG repeats. Altered expression o f genes regulated posttranscriptionally by CUG-BP therefore may contri bute to DM pathogenesis.