Caveolinopathies

Abstract

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.

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

“…Cav-3 protein is 151 amino acids (aa) long and is divided in five separate domains: N-terminal (aa 1-53), scaffolding (aa [54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72][73], transmembrane (aa 74-106), and C-terminal (aa 107-151). The N-terminal domain contains a signature sequence (aa 41-48, FED-VIAEP) that is present in all caveolins.…”

“…This disorder is characterized by a benign clinical course, there is no evidence of respiratory impairment and life expectancy is not reduced. 59 Notably, few CAV3 mutations are associated with LGMD-1C and different clinical phenotypes in the same family, and few patients display overlapping signs between LGMD and RMD. 43,60,61 HyperCKemia Isolated H-CK, that is, increased serum concentration of CK in the absence of any clinical findings of muscular disease can occur in simplex (that is, a single occurrence in a family) or familial cases.…”

“…7 These ultrastructural changes were further confirmed in subsequent reports, including patients affected by DM or RMD. 5,59 Secondarily, functional characterization of few CAV3 mutations (p.P104L, p.DTFT 63-65 p.R26Q and p.T77K) indicated that these mutants form unstable high molecular mass aggregates that are retained in the Golgi complex and are not correctly targeted to the plasma membrane. Consistently with their autosomal-dominant inheritance, these mutations can cause retention of wild-type Cav-3 in the Golgi compartment thus inducing the proteolysis of wild-type Cav-3 by ubiquitination and proteasomal degradation (Figures 3 and 4).…”

“…[1][2][3][4] The critical role of Cav-3 in muscle cell physiology was shown first by in vitro and in vivo studies and was conclusively confirmed by the findings that mutations in caveolin-3 gene (CAV3) lead to distinct neuromuscular and cardiac disorders such as Limb Girdle Muscular Dystrophy (LGMD) 1-C, idiopathic persistent elevation of serum creatine kinase (H-CK), inherited rippling muscle disease (RMD), distal myopathy (MD) and familial hypertrophic cardiomyopathy (HCM). 1,5,6 Notably, over the past few years, mutations in the…”

Caveolin-1, caveolin-3 and VEGF expression in the masticatory muscles of mdx mice

“…Furthermore, cav-3 defects have been closely tied to muscular dystrophy [12]. Mutation in the cav-3 gene causes autosomal dominant muscle diseases [13,14]. Transgenic overexpression of cav-3 has been found to induce a phenotype similar to Duchenne muscular dystrophy (DMD) [15].…”