Caveolinopathies: From the biology of caveolin-3 to human diseases

European journal of human genetics: EJHG (Impact Factor: 4.23). 12/2009; 17(12):1692. DOI: 10.1038/ejhg.2009.147
Source: PubMed

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.

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Available from: Claudio Bruno, Mar 12, 2014
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    • "All caveolins form an hairpin structure that crosses the plasma membrane with the N-and C-terminus domain of the protein facing the cytoplasm. Caveolins are usually found in the majority of mammalian adherent cells, where CAV1 and -2 are mainly expressed in endothelial cells (EC) and adipocytes [Hansen and Nichols, 2010]while CAV3 is referred to as muscle specific, being restricted to skeletal, smooth and cardiac muscle [Gazzerro et al., 2010]. The ability of CAV1 to form homooligomers and heterooligomers with CAV2, typically in the endoplasmic reticulum (ER), and their high affinity for cholesterol and glycosphingolipids are crucial for the insertion of the protein into the plasma membrane and for the formation of flask-like invaginations called caveolae [Sengupta, 2012; Thiele et al., 2000], small non-clathrin coated invaginations found in many cell types [Parton and Simons, 2007]. "
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    ABSTRACT: Caveolin-1 (CAV1) is the principal structural component of caveolae which functions as scaffolding protein for the integration of a variety of signaling pathways. In this study, we investigated the involvement of CAV1 in endothelial cell functions and show that siRNA-induced CAV1 silencing in the human EC line EA.hy926 induces distinctive morphological changes, such as a marked increase in cell size and formation of stress fibers. Design-based stereology was employed in this work to make unbiased quantification of morphometric properties such as volume, length and surface of CAV1 silenced vs. control cells. In addition, we showed that down regulation CAV1 affects cell cycle progression at G1/S phase transition most likely by perturbation of AKT signaling. With the aim to assess the contribution of CAV1 to typical biological processes of EC, we report here that CAV1 targeting affected cell migration and matrix metalloproteinases (MMPs) activity, and reduced angiogenesis in response to VEGF, in vitro. Taken together our data suggest that the proper expression of CAV1 is important not only for maintaining the appropriate morphology and size of endothelial cells but it might represent a prospective molecular target for studying key biological mechanisms such as senescence and tumorigenesis. J. Cell. Biochem. © 2013 Wiley Periodicals, Inc.
    Journal of Cellular Biochemistry 08/2013; 114(8). DOI:10.1002/jcb.24526 · 3.37 Impact Factor
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    • "The histochemical analysis performed on skeletal muscle biopsy revealed reduced immunolabeling for Cav- 3, compatible with diagnosis of caveolinopathy [1]. However , the shoulder girdle involvement presenting with scapular winging observed in our case is unusual in caveolinopathies, although these disorders are associated with a broad spectrum of clinical phenotypes [12] [35]. Beyond the bilateral winged scapula and the limitation of upper arms abduction, the patient also displayed other clinical features reminiscent of FSHD, such as marked asymmetry at MRI imaging of muscle involvement in the legs [36] [37] and the inflammatory infiltration observed in muscle biopsy [38]. "
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    ABSTRACT: We report the first case of a heterozygous T78M mutation in the caveolin-3 gene (CAV3) associated with rippling muscle disease and proximal myopathy. The patient displayed also bilateral winged scapula with limited abduction of upper arms and marked asymmetric atrophy of leg muscles shown by magnetic resonance imaging. Immunohistochemistry on the patient's muscle biopsy demonstrated a reduction of caveolin-3 staining, compatible with the diagnosis of caveolinopathy. Interestingly, consistent with the possible diagnosis of FSHD, the patient carried a 35 kb D4Z4 allele on chromosome 4q35. We discuss the hypothesis that the two genetic mutations may exert a synergistic effect in determining the phenotype observed in this patient.
    Neuromuscular Disorders 01/2012; 22(6):534-40. DOI:10.1016/j.nmd.2011.12.001 · 3.13 Impact Factor
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    • "Cav3 expression must be tightly regulated, as demonstrated by the fact that either a deficiency or an excess causes muscular disorders. In particular, loss of Cav3 at the sarcolemma is a feature sign of caveolinopathies, a heterogeneous group of genetic diseases caused by Cav3 mutations giving rise to dominant-negative protein forms [16] [17] [18] [19] [20]. The missense Cav3 (P104L) substitution is frequently associated to the human limb girdle muscular dystrophy 1-C (LGMD1C, OMIM #607801) [16], and its transgenic delivery causes muscular defects also in mice and zebrafish models [9] [12] [21]. "
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    ABSTRACT: Unbalanced levels of caveolin-3 (Cav3) are involved in muscular disorders. In the present study we show that differentiation of immortalized myoblasts is affected by either lack or overexpression of Cav3. Nevertheless, depletion of Cav3 induced by delivery of the dominant-negative Cav3 (P104L) form elicited a more severe phenotype, characterized by the simultaneous attenuation of the Akt and p38 signalling networks, leading to an immature cell and molecular signature. Accordingly, differentiation of myoblasts harbouring Cav3 (P104L) was improved by countering the reduced Akt and p38 signalling network via administration of IGF-1 or trichostatin A. Furthermore, loss of Cav3 correlated with a deregulation of the TGF-β-induced Smad2 and Erk1/2 pathways, confirming that Cav3 controls TGF-β signalling at the plasma membrane. Overall, these data suggest that loss of Cav3, primarily causing attenuation of both Akt and p38 pathways, contributes to impair myoblast fusion.
    Biochimica et Biophysica Acta 04/2011; 1812(4):468-79. DOI:10.1016/j.bbadis.2010.12.005 · 4.66 Impact Factor
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