Molecular Studies of Ca Channels and the Dystrophin-Glycoprotein Complex 
mal skeletal muscle, but is absent from the mus- 
cle of DMD patients and mdx mice. The pre- 
dicted amino acid sequence of dystrophin 
suggests that it is a membrane cytoskeletal pro- 
tein and, furthermore, that DMD is a disease of 
the membrane cytoskeleton. 
Studies of other genetic diseases involving the 
cytoskeleton have shown that a deficiency in a 
major cytoskeletal component can severely affect 
the integrity of the cell membrane. For example, 
spectrin deficiency results in fragile erythrocyte 
membranes and thus severe hemolytic anemia. 
In comparison, dystrophin has not been consid- 
ered to play a major structural role in the mem- 
brane cytoskeleton of skeletal muscle because of 
its low abundance of approximately 0.002 per- 
cent of total muscle protein. In the past year we 
have determined the cytoskeletal properties and 
relative abundance of dystrophin in a highly puri- 
fied preparation of skeletal muscle sarcolemma. 
We have found that it constituted fully 2 percent 
of the sarcolemma protein. This suggests that it 
does play a major structural role and that the in- 
tegrity of DMD muscle sarcolemma, through lack 
of dystrophin, is likely to be compromised. 
In order to understand the molecular pathogen- 
esis of DMD, it is imperative to identify the pro- 
teins that are associated and/or linked to dystro- 
phin, since the absence of one component of the 
membrane cytoskeleton is sometimes accompa- 
nied by the loss of another. In the past year our 
laboratory has succeeded in purifying a dystro- 
phin-glycoprotein complex from rabbit skeletal 
muscle and identifying five dystrophin-asso- 
ciated proteins, including four glycoproteins. 
In addition to dystrophin, the complex con- 
tains a 59-kDa protein triplet and four glycopro- 
teins of 1 56, 50, 43, and 35 kDa. We have begun 
to characterize the status of these proteins in dys- 
trophin-free muscle. One interesting finding was 
a dramatic (about 90 percent) deficiency of the 
156-kDa dystrophin-associated glycoprotein in 
muscle from mdx mice and DMD patients. Thus 
the marked reduction of the 156-kDa glycopro- 
tein in dystrophic muscle, and possibly of other 
dystrophin-associated proteins, maybe the initial 
step(s) involved in the molecular pathogenesis 
of muscular dystrophy. 
Our goal for the next year is to clone each of 
the dystrophin-associated glycoproteins and de- 
termine their structure and possible function. 
The results should help to define the function of 
dystrophin and explain how its absence results 
in DMD. 
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