Image courtesy of Charles Thornton, University of Rochester Medical Center, USA.

Myotonic dystrophy (or dystrophia myotonica, DM) — the most common adult muscular dystrophy in humans — has a complex, dominantly inherited pathology caused by a triplet repeat (CTG) expansion in the 3′ untranslated region (UTR) of the serine threonine kinase-encoding DMPK gene. Certain aspects of this disorder have been accounted for in previous mouse models of DM, apart from the myotonia (hyperexcitability) of the skeletal muscle. A recent paper now indicates that this characteristic of DM is not mediated by the Dmpk gene itself but by a toxic gain-of-function effect caused by the expanded CUG repeat in the mutant DMPK mRNA.

Because inactivating Dmpk in mice causes muscle weakness but not Myotonia, Mankodi et al. assayed for the phenotypic effects of the untranslated repeat by expressing 250 CUG repeats in the 3′ UTR of a human actin transgene. The expression of this transgene in mouse skeletal muscle caused myotonia by four weeks of age and mortality in 41% of the mice by 44 weeks of age — effects that were not seen in mice expressing a short-repeat actin transgene.

Why is the CUG repeat toxic? So far, this remains unknown. The expanded repeat sequesters the mutant transcript in the nucleus (shown in green and blue, respectively, in the picture), where Mankodi et al. speculate it might interfere with RNA processing or interact with double-stranded RNA-binding proteins. This mouse model should help to unravel the mechanisms behind this toxic effect and, more generally, the role that expanded repeats play in disease pathogenesis.