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Human Molecular Genetics, 2001, Vol. 10, No. 19 2165-2170
© 2001 Oxford University Press

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

Ami Mankodi, Carl R. Urbinati1, Qiu-Ping Yuan2, Richard T Moxley, Valeria Sansone, Matt Krym, Donald Henderson, Martin Schalling2, Maurice S. Swanson1 and Charles A. Thornton+

Department of Neurology, School of Medicine and Dentistry, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642, USA, 1Department of Molecular Genetics and Microbiology, Centers for Gene Therapy and Mammalian Genetics, University of Florida College of Medicine, Gainesville, FL 32610, USA and 2Department of Molecular Medicine, Neurogenetics Unit, Karolinska Hospital, S-17176 Stockholm, Sweden

The phenotypes in myotonic dystrophy types 1 and 2 (DM1 and DM2) are similar, suggesting a shared pathophysiologic mechanism. DM1 is caused by expansion of a CTG repeat in the DMPK gene. Pathogenic effects of this mutation are likely to be mediated, at least in part, by the expanded CUG repeat in mutant mRNA. The mutant transcripts are retained in the nucleus in multiple discrete foci. We investigated the possibility that DM2 is also caused by expansion of a CTG repeat or related sequence. Analysis of DNA by repeat expansion detection methods, and RNA by ribonuclease protection, did not show an expanded CTG or CUG repeat in DM2. However, hybridization of muscle sections with fluorescence-labeled CAG-repeat oligonucleotides showed nuclear foci in DM2 similar to those seen in DM1. Nuclear foci were present in all patients with symptomatic DM1 (n = 9) or DM2 (n = 9) but not in any disease controls or healthy subjects (n = 23). The foci were not seen with CUG- or GUC-repeat probes. Foci in DM2 were distinguished from DM1 by lower stability 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 accumulation of mutant RNA is pathogenic in DM1, suggest that a similar disease process occurs in DM2, and point to a role for muscleblind in the pathogenesis of both disorders.

+ To whom correspondence should be addressed. Tel: +1 716 275 2542; Fax: +1 716 273 1255; Email: charles_thornton@urmc.rochester.edu Present address: Valeria Sansone, Department of Neurology, University of Milan - S. Donato Hospital, Milan, Italy


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