myotonic dystrophy - IDMC.org

Abstract No : 16
ORAL PRESENTATIONS
A REVERSIBLE MULTISYSTEMIC MURINE MODEL
OF MYOTONIC DYSTROPHY TYPE 2
Margolis J.M., Kang Y.L., Zu T., Day J.W. and Ranum L.P.W.
MMC 206, 420 Delaware St. SE, University of Minnesota, Minneapolis, MN 55455, USA
We previously showed that myotonic dystrophy type 2 (DM2) is caused by a large CCTG
repeat expansion in intron 1 of the zinc finger protein 9 (ZNF9) gene. There is growing
evidence that DM1 and DM2 are caused by an RNA gain of function mechanism in which
the CUG and CCUG expansions cause the multisystemic features of these diseases by
directly altering RNA processing. To investigate the role that expression of the CCUG
transcripts play in the multisystemic DM phenotype, and to avoid problems such as
infertility that have complicated previous systemic models of DM1, we have developed
a tetracycline inducible murine model of the DM2 CCUG expansion. In our expansion
lines, the expression of a CCTG repeat tract with 300 repeats is driven by a tet-responsive
(TRE)/minimal CMV promoter as part of a non-coding transcript. These TRE-CCTG
expansion lines have been crossed to tet-activator (tTA) mice in which the tTA is controlled
by a CMV promoter. Doubly transgenic mice TRE-CCTG / CMV-tTA mice ubiquitously
express CCUG expansion transcripts in the absence of doxycycline. Routine H&E staining
of muscle from these doubly transgenic animals shows variation in fiber size and
centrally located nuclei indicative of myopathy. Additionally, skeletal muscle shows
ribonuclear inclusions and aberrant splicing of the insulin receptor (IR) by RT-PCR analysis,
which has not previously been reported in mouse models of DM1. Like DM1 and DM2
patient biopsies, the predominant IR isoform in muscle from these mice excludes exon
11 which leads to a preferential expression of the insulin insensitive isoform. Further,
aberrant splice patterns of cTNT are observed by RT-PCR from cardiac muscle indicating
that the CCUG expansion transcripts in this model affect both cardiac and skeletal muscle.
In a separate series of experiments the TRE-CCUG expansion lines described above
will be crossed to two different BAC transgenic lines engineered to drive expression of
the tTA using the endogenous human DMPK or ZNF9 promoters. Phenotypic characterization
of these doubly transgenic mice will help determine the extent to which the clinical
similarities and differences, including developmental differences between DM1 and
DM2, result from differences in the temporal and spatial expression patterns of the
repeat containing transcripts driven by the ZNF9 and DMPK promoters.
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