Muscleblind localizes to nuclear foci of aberrant RNA in myotonic dystrophy types 1 and 2

The phenotypes in myotonic dystrophy types 1 and 2 (DM1 and DM2) are simila r, suggesting a shared pathophysiologic mechanism. DM1 is caused by expansi on of a CTG repeat in the DMPK gene. Pathogenic effects of this mutation ar e likely to be mediated, at least in part, by the expanded CUG repeat in mu tant mRNA. The mutant transcripts are retained in the nucleus in multiple d iscrete foci. We investigated the possibility that DM2 is also caused by ex pansion of a CTG repeat or related sequence. Analysis of DNA by repeat expa nsion detection methods, and RNA by ribonuclease protection, did not show a n expanded CTG or CUG repeat in DM2. However, hybridization of muscle secti ons with fluorescence-labeled CAG-repeat oligonucleotides showed nuclear fo ci in DM2 similar to those seen in DM1. Nuclear foci were present in all pa tients with symptomatic DM1 (n = 9) or DM2 (n = 9) but not in any disease c ontrols or healthy subjects (n = 23). The foci were not seen with CUG- or G UC-repeat probes. Foci in DM2 were distinguished from DM1 by lower stabilit y of the probe-target duplex, suggesting that a sequence related to the DM1 CUG expansion accumulates in the DM2 nucleus. Muscleblind proteins, which interact with expanded CUG repeats in vitro, localized to the nuclear foci in both DM1 and DM2. These results support the idea that nuclear accumulati on of mutant RNA is pathogenic in DM1, suggest that a similar disease proce ss occurs in DM2, and point to a role for muscleblind in the pathogenesis o f both disorders.