Expanded-repeat-RNA-mediated disease mechanisms in myotonic dystrophy

Myotonic dystrophy (DM) is the most common muscular dystrophy in adults, affecting skeletal muscle as well as cardiac and smooth muscle. Furthermore, involvement of the central nervous system, endocrine organs, and eyes is often seen, with debilitating consequences. The condition is an autosomal-dominant inherited genetic disease caused by abnormal genomic expansion of tandem repeats. Myotonic dystrophy type 1 (DM1) results from expansion of a CTG repeat in the 3'-untranslated region of the gene encoding dystrophia myotonica-protein kinase (DMPK), whereas myotonic dystrophy type 2 (DM2) is caused by expansion of a CCTG repeat in the first intron of the gene encoding CCHC-type zinc finger nucleic acid-binding protein (CNBP). Both types of DM exhibit abnormal mRNA transcribed from the mutated gene containing expanded repeats, which exert toxic gain-of-function effects on various proteins involved in cellular processes such as alternative splicing, signaling pathways, and cellular senescence. The present review discusses the expanded-repeat-RNA-mediated molecular pathomechanisms in DM.