TRANSGENIC MDX MICE EXPRESSING DYSTROPHIN WITH A DELETION IN THE ACTIN-BINDING DOMAIN DISPLAY A MILD BECKER PHENOTYPE

The functional significance of the actin-binding domain of dystrophin, the protein lacking in patients with Duchenne muscular dystrophy, has remained elusive. Patients with deletions of this domain (domain I) t ypically express low levels of the truncated protein. Whether the mode rate to severe phenotypes associated with such deletions result from l oss of an essential function, or from reduced levels of a functional p rotein, is unclear. To address this question, we have generated transg enic mice that express wild-type levels of a dystrophin deleted for th e majority of the actin binding domain. The transgene derived protein lacks amino acids 45-273, removing 2 of 3 in vitro identified actin in teracting sites and part of hinge 1. Examination of the effect of this deletion in mice lacking wild-type dystrophin (mdx) suggests that a f unctional domain I is not essential for prevention of a dystrophic phe notype. However, in contrast to deletions in the central rod domain an d to full-length dystrophin, both of which are functional at only 20 % of wild-type levels, proteins with a deletion in domain I must be exp ressed at high levels to prevent a severe dystrophy. These results are also in contrast to the severe dystrophy resulting from truncation of the COOH-terminal domain that links dystrophin to the extracellular m atrix. The mild phenotype observed in mice with domain I-deletions ind icates that an intact actin-binding domain is not essential, although it does contribute to an important function of dystrophin. These studi es also suggest the link between dystrophin and the subsarcolemmal cyt oskeleton involves more than a simple attachment of domain I to actin filaments.