Human Molecular Genetics, 2002, Vol. 11, No. 16 1807-1815
© 2002 Oxford University Press
Spectrin-like repeats from dystrophin and 
-actinin-2 are not functionally interchangeable
1Department of Neurology, University of Washington School of Medicine, HSB Room K243, Box 357720, Seattle, WA 98195-7720, USA and 2Program in Cellular and Molecular Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA
Received March 3, 2002; Revised May 8, 2002; Accepted May 18, 2002
Mutations in the dystrophin gene result in Duchenne muscular dystrophy (DMD). Dystrophin is a multidomain protein that functions to stabilize the sarcolemmal membrane during muscle contraction. The central rod domain has been proposed to act as a shock absorber, as a force transducer or as a spacer separating important N- and C-terminal domains that interact with actin and the dystrophin–glycoprotein complex (DGC). Structure/function studies demonstrated that deletion of large portions of the rod domain can result in the production of smaller, yet highly functional, dystrophin proteins. In a dramatic example, a ‘micro-dystrophin’ transgene containing only four dystrophin spectrin-like repeats resulted in complete correction of most of the symptoms associated with dystrophy in the mdx mouse model for DMD. Dystrophin shares considerable homology with the multidomain, actin-crosslinking protein 
-actinin. To explore the hypothesis that the dystrophin rod domain acts as a spacer region, a chimeric micro-dystrophin transgene containing the four-repeat rod domain of -actinin-2 was expressed in mdx mice. This chimeric transgene was incapable of correcting the morphological pathology of the mdx mouse, but still functioned to assemble the DGC at the membrane and provided some protection from contraction-induced injury. These data demonstrated that different spectrin-like repeats are not equivalent, and reinforced the suggestion that the dystrophin rod domain is not merely a spacer but likely contributes an important mechanical role to overall dystrophin function.
* To whom correspondence should be addressed. Tel: +1 2062215363; Fax: +1 2066168272; Email: jsc5{at}u.washington.edu
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