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Caveolinopathies

Mutations in caveolin-3 cause four distinct autosomal dominant muscle diseases

From the Department of Molecular Pharmacology (Drs. Woodman, Sotgia, and Lisanti), Albert Einstein College of Medicine, Bronx, NY; Department of Pharmacology (Dr. Galbiati), University of Pittsburgh School of Medicine, PA; and Neuromuscular Disease Unit, Department of Pediatrics (Dr. Minetti), University of Genova, Gaslini Institute, Italy.

Address correspondence and reprint requests to Dr. Michael P. Lisanti, Department of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461; e-mail: lisanti{at}aecom.yu.edu

The caveolin-3 protein is expressed exclusively in muscle cells. Caveolin-3 expression is sufficient to form caveolae-sarcolemmal invaginations that are 50 to 100 nm in diameter. Monomers of caveolin-3 oligomerize to form high molecular mass scaffolding on the cytoplasmic surface of the sarcolemmal membrane. A mutation in one caveolin-3 allele produces an aberrant protein product capable of sequestering the normal caveolin-3 protein in the Golgi apparatus of skeletal muscle cells. Improper caveolin-3 oligomerization and membrane localization result in skeletal muscle T-tubule system derangement, sarcolemmal membrane alterations, and large subsarcolemmal vesicle formation. To date, there have been eight autosomal dominant caveolin-3 mutations identified in the human population. Caveolin-3 mutations can result in four distinct, sometimes overlapping, muscle disease phenotypes: limb girdle muscular dystrophy, rippling muscle disease, distal myopathy, and hyperCKemia. Thus, the caveolin-3 mutant genotype-to-phenotype relation represents a clear example of how genetic background can influence phenotypic outcome. This review examines in detail the reported cases of patients with caveolin-3 mutations and their corresponding muscle disease phenotypes.

Received May 28, 2003. Accepted in final form October 14, 2003.

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