February 11, 2008

New MMD Mouse Adds to Understanding of Disease

MDA grantee Thomas Cooper at Baylor College of Medicine, with colleagues there and in France, has added a new piece to the puzzle oftype 1 myotonic dystrophy (MMD1) that may help explain some of the differences between it and the type 2 form of the disease (MMD2), and could ultimately lead to treatment advances.

Cooper, a professor of pathology and of molecular and cellular biology, coordinated the research team, which will publish its findings in the Feb. 19, 2008, issue of Proceedings of the National Academy of Sciences.

The investigators first bred mice with a large expanded stretch of DNA in the DMPK gene, the same defect in the same location as the one that causes human MMD1. They say these mice mimic the human disease better than most other “mouse models” of MMD1 because, in addition to myotonia (inability to relax muscles) and characteristic molecular abnormalities, these mice exhibit severe muscle wasting (atrophy), as observed in the human disease. (In 2001, Genevieve Gourdon at Necker Hospital in Paris coordinated a team that developed an MMD mouse model with a shorter expansion in the DMPK gene that also mimicked human MMD, but these mice showed only subtle muscle atrophy.)

Most previously developed mouse models of MMD1 have added the expanded DNA (which consists of chains of repeated DNA sequences) to a gene other than DMPK; or have inserted high numbers of normal-length repeated DNA pieces instead of a long, repeated DNA expansion; or have mimicked a secondary effect of the DNA expansion, the depletion of a protein known as MBNL1.

Cooper and colleagues say these other models exhibit some of the features and molecular events seen in human MMD1, but not all. They say their new model is the only one to mimic the muscle wasting that patients have and to show elevated levels of a protein called CUGBP1 in muscle cells, another characteristic of human MMD1.

They note that people with MMD2, which involves an expanded stretch of repeated DNA sequences in a gene other than DMPK, don’t have high levels of CUGBP1 and typically have milder muscle wasting than people with MMD1.

The increase in CUGBP1 levels, which has deleterious effects on muscle tissue and correlates with the severe muscle atrophy, seem to occur only when the expanded DNA sections are in the DMPK gene and not when they’re in other genes.

The study challenges a widely held view that the location of the expanded DNA stretch isn’t important in either type of MMD and that its existence in any location would cause roughly the same problems.