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Review
, 18 (2), 137-45

Caveolinopathies: From the Biology of caveolin-3 to Human Diseases

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Review

Caveolinopathies: From the Biology of caveolin-3 to Human Diseases

Elisabetta Gazzerro et al. Eur J Hum Genet.

Erratum in

  • Eur J Hum Genet. 2009 Dec;17(12):1692

Abstract

In muscle tissue the protein caveolin-3 forms caveolae--flask-shaped invaginations localized on the cytoplasmic surface of the sarcolemmal membrane. Caveolae have a key role in the maintenance of plasma membrane integrity and in the processes of vesicular trafficking and signal transduction. Mutations in the caveolin-3 gene lead to skeletal muscle pathology through multiple pathogenetic mechanisms. Indeed, caveolin-3 deficiency is associated to sarcolemmal membrane alterations, disorganization of skeletal muscle T-tubule network and disruption of distinct cell-signaling pathways. To date, there have been 30 caveolin-3 mutations identified in the human population. Caveolin-3 defects lead to four distinct skeletal muscle disease phenotypes: limb girdle muscular dystrophy, rippling muscle disease, distal myopathy, and hyperCKemia. In addition, one caveolin-3 mutant has been described in a case of hypertrophic cardiomyopathy. Many patients show an overlap of these symptoms and the same mutation can be linked to different clinical phenotypes. This variability can be related to additional genetic or environmental factors. This review will address caveolin-3 biological functions in muscle cells and will describe the muscle and heart disease phenotypes associated with caveolin-3 mutations.

Figures

Figure 1
Figure 1
Cav-3 is synthesized in the endoplasmic reticulum (ER) and is then transported to the Golgi complex as detergent-soluble oligomers. When Cav-3 exits the Golgi complex, the oligomers associate with glycosphingolipid and cholesterol-enriched lipid-raft domains, as judged by detergent-resistant membrane (DRM) association, and forms the caveolar carriers. These complexes finally fuse with the plasma membrane defining the caveolae invaginations.
Figure 2
Figure 2
CAV3 mutations cause a severe decrease in Cav-3 expression and membrane localization. (a) Frozen sections of the skeletal muscle biopsy from one representative patient (Pt) and an age-matched control (C) were prepared and immunostained with specific antibodies against caveolin-3 (Cav-3). In control muscle Cav-3 displays a uniform pattern at the sarcolemma. In the patient, Cav-3 is markedly reduced. Final magnification, × 40. (b) Protein lysates prepared from the skeletal muscle biopsy from one patient (Pt) and an age-matched control (C) were separated by SDS-PAGE and subjected to western immunoblot analysis using antibodies against Cav-3. In the patient Cav-3 protein levels are reduced by approximately 80%. Modified and reproduced by Traverso et al.
Figure 3
Figure 3
Cav-3 mutants are retained in an intracellular compartment and are expressed at lower levels. Cos-7 cells were transiently transfected with cDNA encoding either for Cav-3 wild type (WT) or the Cav-3 mutant T78K. (a) Thirty-six hours post-transfection, cells were fixed and stained with antibodies against Cav-3. Cav-3 WT is localized at the plasma membrane, as expected, whereas Cav-3 T78K is retained in an intracellular, perinuclear compartment. N, nucleus. Final magnification, × 100. (b) Thirty-six hours post-transfection, cells were extracted and protein lysates subjected to western immunoblot analysis with antibodies against Cav-3. Cav-3 T78K is expressed at much lower levels than Cav-3 WT. Modified and reproduced by Traverso et al.
Figure 4
Figure 4
Cav-3 mutants cause the intracellular retention of Cav-3 wild-type form. Cos-7 cells were transiently co-transfected with cDNA encoding GFP-Cav-3 wild type (WT) in combination either with Cav-3 WT or the Cav-3 T78K mutant. Thirty-six hours post-transfection, cells were fixed and stained with antibodies against GFP. When co-transfected with Cav-3 WT or GFP-Cav-3 WT is localized at the plasma membrane, as expected. When co-transfected with Cav-3 T78K, GFP-Cav-3 WT is retained in a perinuclear compartment, suggesting that Cav-3 T78K behaves in a dominant-negative manner. N, nucleus. Final magnification, × 100. Modified and reproduced by Traverso et al.

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