Myotonic dystrophy: RNA pathogenesis comes into focus

Abstract

Myotonic dystrophy (DM)--the most common form of muscular dystrophy in adults, affecting 1/8000 individuals--is a dominantly inherited disorder with a peculiar and rare pattern of multisystemic clinical features affecting skeletal muscle, the heart, the eye, and the endocrine system. Two genetic loci have been associated with the DM phenotype: DM1, on chromosome 19, and DM2, on chromosome 3. In 1992, the mutation responsible for DM1 was identified as a CTG expansion located in the 3' untranslated region of the dystrophia myotonica-protein kinase gene (DMPK). How this untranslated CTG expansion causes myotonic dystrophy type 1(DM1) has been controversial. The recent discovery that myotonic dystrophy type 2 (DM2) is caused by an untranslated CCTG expansion, along with other discoveries on DM1 pathogenesis, indicate that the clinical features common to both diseases are caused by a gain-of-function RNA mechanism in which the CUG and CCUG repeats alter cellular function, including alternative splicing of various genes. We discuss the pathogenic mechanisms that have been proposed for the myotonic dystrophies, the clinical and molecular features of DM1 and DM2, and the characterization of murine and cell-culture models that have been generated to better understand these diseases.

Figure 1

RNA in situ hybridization of the expansion. A, In situ hybridization of CAGG probe to DM2 muscle. B, In situ hybridization of CAGG probe to normal muscle. C, In situ hybridization of CAG probe to DM1 muscle. The scale bar is 5 μM. (Reprinted from Science 293:864–867.)

Figure 2

RNA model of DM pathogenesis. The unusual and rare multisystemic clinical parallels between DM1 and DM2 suggest a similar pathogenic mechanism. The discovery that DM2 mapped to chromosome 3 and not the DM1 region of chromosome 19 make it unlikely that regional effects of gene expression play a major role in causing the common clinical features of the disease because regional disregulation would affect different sets of genes. The discovery that a CCTG repeat expansion located on chromosome 3 which is expressed at the RNA but not the protein level causes DM2, and the observation that both CUG and CCUG repeat–containing foci accumulate in affected muscle nuclei suggests that a gain-of-function RNA mechanism underlies the clinical features common to both diseases. Specific changes in pre-mRNA splicing have been that have been associated with several genes, including the insulin receptor, the chloride channel, and cardiac troponin T, are correlated with insulin resistance, myotonia, and possibly cardiac abnormalities. (Adapted from Curr Opin Genet Dev 12:266–271.)

Figure 3

Schematic diagram of steps involved in RNA gain-of-function mechanism. CTG and CCTG expansions at the DM1 or DM2 loci result in the accumulation of CUG or CCUG repeat–containing transcripts as nuclear RNA foci. RNA-binding proteins, including CUG-BP and the muscleblind family of proteins bind to or are disregulated by the repeat-containing RNA transcripts resulting in specific trans-alterations in pre-mRNA splicing.