Caveolinopathies: mutations in caveolin-3 cause four distinct autosomal dominant muscle diseases.
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.
Woodman
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Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Sotgia
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Galbiati
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Minetti
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Lisanti
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MP
D000368:Aged; D000595:Amino Acid Sequence; D051244:Caveolin 3; D022461:Caveolins / Q000235:genetics* / Q000502:physiology; D002648:Child; D002675:Child, Preschool; D003402:Creatine Kinase / Q000097:blood*; D005260:Female; D005799:Genes, Dominant; D005838:Genotype; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009119:Muscle Contraction; D009135:Muscular Diseases / Q000235:genetics*; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics*; D009154:Mutation; D009468:Neuromuscular Diseases / Q000097:blood / Q000235:genetics; D010641:Phenotype; D012508:Sarcolemma / Q000737:chemistry / Q000648:ultrastructure
C417736:CAV3 protein, human; D051244:Caveolin 3; D022461:Caveolins; D003402:Creatine Kinase