Expanded CUG Repeats Dysregulate RNA Splicing by Altering the Stoichiometry of the Muscleblind 1 Complex

To understand the role of the splice regulator muscleblind 1 (MBNL1) in the development of RNA splice defects in myotonic dystrophy I (DM1), we purified RNA-independent MBNL1 complexes from normal human myoblasts and examined the behavior of these complexes in DM1 myoblasts. Antibodies recognizing MBNL1 variants (MBNL1CUG), which can sequester in the toxic CUG RNA foci that develop in DM1 nuclei, were used to purify MBNL1CUG complexes from normal myoblasts. In normal myoblasts, MBNL1CUG bind 10 proteins involved in remodeling ribonucleoprotein complexes including hnRNP H, H2, H3, F, A2/B1, K, L, DDX5, DDX17, and DHX9. Of these proteins, only MBNL1CUG colocalizes extensively with DM1 CUG foci (>80% of foci) with its partners being present in