SARCOLEMMAL EXPRESSION OF DYSTROPHIN C-TERMINUS BUT REDUCED EXPRESSION OF 6Q-DYSTROPHIN-RELATED PROTEIN IN 2 DMD PATIENTS WITH LARGE DELETIONS OF THE DYSTROPHIN GENE

Partial deletions of the dystrophin gene are the predominant genetic l esions in Duchenne (DMD) and Becker (BMD) muscular dystrophies. Accord ing to the reading frame hypothesis [1], any deletion disrupting the t ranslational reading frame of the mRNA cannot result in expression of the dystrophin molecule and should lead to severe phenotypes of DMD. I n contrast, deletions which maintain the reading frame across the dele ted exons may give rise to truncated, semifunctional proteins and mild er courses of the disease (i.e. BMD). Among the notable exceptions of this hypothesis are very large ''in-frame'' deletions by which functio nally indispensable domains of the dystrophin molecule have been remov ed. Here, we report on two DMD patients with large intragenic in-frame deletions. Grossly truncated, but stable dystrophin molecules with pr eserved C-terminal domains were detected at the sarcolemma on cryosect ions in both patients. However, dystrophin organization on single-teas ed muscle fibers revealed disarrangement of the costameric pattern, if compared to normal skeletal muscle fibers. Compared to dystrophin-def icient DMD muscle. expression of chromosome-6-encoded dystrophin-relat ed protein (DRP) was greatly diminished in skeletal muscle of both pat ients. We show, that loss of more than 50% of dystrophin seems to be d eleterious for the protein's function and therefore, the extent of the deletions may have an impact on construction of dystrophin mini genes . Moreover, these findings shed new light on the functional significan ce of the C-terminal domain of dystrophin. They also suggest a negativ e correlation between sarcolemmal expression of the dystrophin C-termi nus and DRP expression at the sarcolemma.