Myotonic Dystrophy Type 2
Myotonic Dystrophy 2 (DM2) is a muscular disease clinically related to Myotonic Dystrophy 1 (DM1) but associated with the expansion of CCTG repeats in intron 1 of the zinc finger factor encoding gene, ZNF9, on chromosome 3q. While some symptoms in the patients with DM1 and DM2 are similar, several distinct features were described for DM2. These features include lack of congenital form of disease, involvement of different muscles, lack of correlation between age of onset and number of CCTG repeats and lack of genetic anticipation. These specific features of DM2 suggest differences in molecular mechanisms of DM1 and DM2.
We have identified specific mega CCUG-protein complexes in nuclei and in cytoplasm of muscle cells. These protein complexes are formed only on CCUG expansion but not on CUG repeats. Detailed analysis of CCUG-mega complex purified from cytoplasm showed that this complex is formed by protein-protein and RNA-protein interactions. These data suggest that, in addition to CUGBP1 and MBNL1, other proteins are bound to CCUG RNA in DM2. These novel proteins might directly interact with CCUG repeats or might be delivered to complexes via protein-protein interactions.
The project is focused on the identification and analysis of these CCUG- binding protein-protein complexes. Identification of other proteins interacting with CCUG expansion in cytoplasm and in nuclei will allow determining pathways which have been misregulated by expanded CCUGn repeats.
Relevance of the project to IDDRC mission:
Identification of protein-protein complexes binding to CCUG RNA will elucidate pathological pathways mediated by CCUG RNA, but not by CUG RNA, and will help to develop therapy for DM2 disease in all affected tissues including brain.