Molecular Mechanisms of Myotonic Dystrophy: RNA-Mediated Pathogenesis and RNA-Binding Proteins

Since the identification of a repeat expansion as a causative mutation of myotonic dystrophy (dystrophia myotonica, DM) type 1 (DM1), several pathomechanisms have been proposed. Among them, an RNA-mediated mechanism is thought to play a central role in the pathogenesis of DM. In both DM1 and DM type 2 (DM2), mutated alleles produce transcripts containing an expanded CUG (DM1) or CCUG (DM2) tract. These aberrant RNAs accumulate in nuclei and form ribonuclear inclusions or nuclear RNA foci, a pathological hallmark of DM. These transcripts sequester muscleblind-like (MBNL) proteins, which regulate alternative splicing and other RNA processing. Loss of function of MBNL proteins in mouse models recapitulates many aspects of DM. In this chapter, the pathomechanisms of DM1 and DM2 are discussed, with an emphasis on the roles of RNA-binding proteins together with recent findings in this field.