Expansion of a CTG repeat sequence located in a gene rich region on chromosome 19ql3.3 results in the neuromuscular disorder, myotonic dystrophy (DM). As the expansion is not found in the coding region of a gene the mechanistic basis of DM has remained a puzzle. Two current models hypothesize that CTG expansion may result in deleterious cis-effects that alter gene transcription in its vicinity and/or have toxic effects that are intrinsic to the repeat sequence. To test these mechanistic models mouse strains encoding large CTG expansions have been developed. Transgenic mice in which CTG expansions have been knocked into the dm locus will be used to characterize the phenotypic consequence of the cis effects of CTG expansion and the intrinsic toxicity of the repeat sequences. Mice encoding expansions of 500 and 2000 repeats at the dm locus will be used to test the hypothesis that cis effects that alter gene transcription in the vicinity of the expansion, progressively spread across the chromosome to boundaries that are dictated by the size of the repeat tract. Toxic effects of the CTG/CUG repeat expansion will be independently characterized in mice encoding expanded CTG tracts integrated at random loci in the genome under the transcriptional control of the human beta actin promoter. We will test the hypothesis that an increased frequency of double-strand breaks in the CTG repeat tracts or pre-mRNA splicing abnormalities resulting from the titration of the splicing factor CUG-BP by the expanded CUG repeats are the molecular mechanism whereby expanded CTG/CUG repeats result in DM pathology.
| Wakimoto, Hiroko; Maguire, Colin T; Sherwood, Megan C et al. (2002) Characterization of cardiac conduction system abnormalities in mice with targeted disruption of Six5 gene. J Interv Card Electrophysiol 7:127-35 |
