Myotonic dystrophy (DM) is caused by the expansion of a trinucleotide repeat located in the 3’-untranslated region of a serine-threonine kinase (DMPK), such that repeat size corresponds with severity of disease and age of onset. The mechanism by which this mutation causes DM remains unclear. Recent reports indicate that over-expression of DMPK in murine C2C12 myoblasts inhibits myogenesis, reminiscent of the marked immaturity observed in DM patient muscle. Accordingly, we generated transgenic mice over-expressing the human DMPK gene with expression enhancing matrix attachment region (MAR) sequences. These mice show substantial over-expression of human DMPK transcript and protein in brain, skeletal muscle, tongue, and eye - tissues typically affected in DM. Cryostat sections of skeletal muscle from these transgenic animals revealed diagnostic hallmarks of DM including increased centronucleation, type 1 fiber atrophy and ringed fibers. Additionally, primary myoblasts established from these mice showed reduced fusion potential indicating a delay or defect in myoblast differentiation. These results suggest that over-expression of the human DMPK gene in these mice confers a skeletal muscle pathology similar to that seen in DM patients.

Myotonic dystrophy is caused by a (CTG) n trinucleotide repeat expansion located in the 3′ untranslated region of the myotonic dystrophy protein kinase gene ( DMPK ). To date, the disease mechanism has proven elusive. The mutation would not be expected to affect kinase function and yet the disease is inherited in a dominant fashion. Mutant DMPK transcripts have been demonstrated to be retained in affected cell nuclei which could reduce DMPK protein levels and cause disease by haploinsufficiency. An alternate hypothesis is that the expansion confers a toxic gain of function on the transcript. In previous studies, various 52–55 kDa proteins have been detected using antisera targeted against DMPK and a decline of two of these candidates in disease tissues was reported. Current information now suggests that these proteins are not products of the myotonic dystrophy gene. We have characterised an antiserum which has been confirmed to recognise authentic 71 and 80 kDa isoforms of DMPK. Determination of the kinase levels in disease tissues with controls for patient age and tissue integrity demonstrates a modest overexpression in adult patients. In tissues from severely affected congenital patients only a slight decline is seen. This data argues against DMPK haploinsufficiency as a disease mechanism.