Muscular dystrophy: defective inhibitor?

Muscular dystrophy: Defective inhibitor?

A recent description of the gene that causes Duchenne musculardystrophy (DMD) has intensified the search for a protein for which that gene codes -- possibly a muscle protein absent or defective in the muscle-wasting disease (SN: 10/25/86, p.261). Identifying the gene product could lead to replacement therapy and a halt to muscle loss. A report in the October BIOCHEMISTRY AND CELL BIOLOGY from scientists at the University of Windsor in Ontario suggests the sought-after gene product may indeed be a defective protein -- more specifically, an inhibitor that fails to inhibit tissue destruction by enzymes called proteases.

Increased protease activity in skeletal muscle, along withloss of muscle proteins and mass, is characteristic of muscular dystrophy in both humans and animals. From mice with a non-DMD form of dystrophy, the researchers have purified an abnormal protease inhibitor that is unable to stop muscle destruction by some classes of proteases. Theoretically, if a defective inhibitor is pinpointed as the cause of the disease, researchers could replace it with a specific, normal inhibitor.

Some experts, however, say it is unlikely that the similaritiesbetween the mouse model used in the Ontario study and DMD are adequate to consider the abnormal inhibitor an insight into the human disease. For example, the mouse model does not carry the disease on the X chromosome, unlike the sex-linked DMD. According to Anthony P. Monaco, a member of the Harvard Medical School group that described the DMD gene last year, "it is likely that we are talking about different genes, different diseases," and that the human form may result from something other than a protease inhibitor problem.

In experiments this month that may answer some of thesequestions, the Ontario group is cloning the mouse MD gene, as well as assaying for abnormal inhibitor in tissue from humans with a non-Duchenne, slow-onset type of muscular dystrophy. As pointed out by Donald Wood of the New York-based Muscular Dystrophy Association of America, the inhibitor concept is "novel," because it is the regulation of the proteases, not the proteases themselves, that is abnormal.