Disease relevance of CAV3

• Mutations in CAV3 have also been described in limb-girdle muscular dystrophy type 1C (LGMD1C; refs. 6,7), demonstrating the allelism of dystrophic and non-dystrophic muscle diseases [1].
• Heterozygous missense mutations in the caveolin-3 gene (CAV3) cause different muscle disorders [2].
• Most patients with CAV3 alterations present with rippling muscle disease (RMD) characterized by signs of increased muscle irritability without muscle weakness [2].
• Mutations in the gene encoding caveolin-3 (CAV3) underlie four distinct disorders of skeletal muscle: the autosomal dominant form of limb-girdle muscular dystrophy type 1C (LGMD-1C), rippling muscle disease (RMD), sporadic and familial forms of hyperCKemia, and distal myopathy [3].
• We screened 663 patients with various phenotypes of unknown etiology, for caveolin-3 protein deficiency, and we identified eight unreported caveolin-deficient patients (from seven families) in whom four CAV3 mutations had been detected (two are unreported) [4].

Psychiatry related information on CAV3

• Caveolin-3 upregulation activates beta-secretase-mediated cleavage of the amyloid precursor protein in Alzheimer's disease [5].

High impact information on CAV3

• The Cav3 subtypes can be differentiated by their kinetics and sensitivity to block by Ni2+ [6].
• Mutations in CAV3 cause mechanical hyperirritability of skeletal muscle in rippling muscle disease [1].
• We found missense mutations in positional candidate CAV3 (encoding caveolin 3; ref. 5) in all five families analyzed [1].
• These mutations may interfere with caveolin-3 oligomerization and disrupt caveolae formation at the muscle cell plasma membrane [7].
• Highlights include the identification of new caveolin family members, the characterization of VIP21-caveolin as a cholesterol-binding oligomeric protein, and evidence for functional interactions between caveolins and heterotrimeric G proteins [8].

Chemical compound and disease context of CAV3

• The authors report a novel sporadic mutation in the CAV3 gene in two unrelated children with persistent elevated levels of serum creatine kinase (hyperCKemia) without muscle weakness [9].

Biological context of CAV3

• We localized the human caveolin-3 gene (CAV3) to chromosome 3p25 and identified two mutations in the gene: a missense mutation in the membrane-spanning region and a micro-deletion in the scaffolding domain [7].
• Sequence analysis of the two coding exons of CAV3 revealed a hitherto unreported heterozygous C82A transversion in the first exon, predicting a Pro28Thr amino acid exchange [10].
• These observations also suggest the presence of factors independent of the CAV3 gene locus that modify phenotype [11].
• We isolated the gene for human caveolin-3 and mapped it to chromosome 3p25 [12].
• Amino acid sequence analysis of the dysferlin protein reveals seven sites that correspond to caveolin-3 scaffold-binding motifs, and one site that is a potential target to bind the WW domain of the caveolin-3 protein [13].

Anatomical context of CAV3

• A CAV3 microdeletion differentially affects skeletal muscle and myocardium [3].
• Caveolin-3 is another skeletal muscle membrane protein which is important in the formation of caveolae and whose mutations cause dominantly inherited limb girdle muscular dystrophy type 1C (LGMD1C) [13].
• Dysferlin shows only partial overlap with Cav-3 on the surface of isolated muscle fibers but co-localizes with Cav-3 in developing transverse (T)-tubules in muscle cell lines [14].
• Caveolin-3 mRNA is expressed predominantly in muscle tissue-types (skeletal muscle, diaphragm, and heart) and is selectively induced during the differentiation of skeletal C2C12 myoblasts in culture [15].
• Caveolin 3 is a principal structural protein of caveolae membrane domains in striated muscle cells and cardiac myocytes [16].

Associations of CAV3 with chemical compounds

• RESULTS: CAV3 genetic analysis showed a heterozygous 3-bp microdeletion (328-330del) in affected individuals, resulting in the loss of a phenylalanine (Phe97del) in the transmembrane domain [3].
• Gene analysis disclosed a heterozygous 80 G-->A substitution in the caveolin-3 gene that was identical to that of reported cases of elevated serum creatine kinase [17].
• Genetic analysis revealed a new heterozygous mutation in the caveolin-3 (CAV-3) gene: a C-->T transition at nucleotide position 83 in exon 1 leading to a substitution of a proline for a leucine at amino acid position 28 (P28L) [18].
• In accordance with these observations, caveolin-3 mutants formed oligomers of a much larger size than wild type caveolin-3 and were excluded from caveolae-enriched membrane fractions as seen by sucrose density gradient centrifugation [19].
• Here, we studied by electron microscopy, including freeze-fracture and lanthanum staining, the distribution of caveolae and the organization of the T-tubule system in caveolin-3 deficient human muscle fibers [20].

Physical interactions of CAV3

• We report that dysferlin co-immunoprecipitates with caveolin-3 from biopsied normal human skeletal muscles [13].
• Cholesterol chelation in vesicles decreased NCX1 transport activity and caveolin-3 co-precipitation [21].

Co-localisations of CAV3

• Sarcolemmal FAT/CD36 in human skeletal muscle colocalizes with caveolin-3 and is more abundant in type 1 than in type 2 fibers [22].

Regulatory relationships of CAV3

• Caveolin-1 and caveolin-2 are expressed in a wide range of cell types whereas caveolin-3 is thought to be a muscle-specific subtype [23].
• We found that overexpression of caveolin-3 augmented insulin-stimulated phosphorylation of insulin receptor substrate-1 in 293T cells but not the phosphorylation of insulin receptor [24].
• CAV3 mutations were engineered using site-directed mutagenesis and heterologously expressed in HEK293 cell lines stably expressing the SCN5A-encoded cardiac sodium channel [25].

Other interactions of CAV3

• The immunoprecipitation data are consistent with the parallel observation that dysferlin immunostaining is not normal in LGMD1C muscles [13].
• Caveolin-3 transcript levels increased in 82% of the cohort, along with a 2.5-fold induction of caveolin-2 [26].
• Human caveolin 3 protein contains the 'caveolin signature sequence' and the 33 amino acids spanning intramembrane domain common to all caveolins [27].
• Furthermore, we provide evidence that FAT/CD36 expression is significantly higher in type 1 compared with type 2 fibers, whereas caveolin-3 expression is significantly higher in type 2 fibers than in type 1 fibers [22].
• We show that (i) these BACs contain all four exons of the oxytocin receptor gene and (ii) that the genes encoding caveolin-3 and the oxytocin receptor are located approximately 7-10 kb apart and in the opposite orientation [28].

Analytical, diagnostic and therapeutic context of CAV3

• Molecular cloning of caveolin-3, a novel member of the caveolin gene family expressed predominantly in muscle [15].
• Caveolin-3 localization was demonstrated by immunohistochemistry [26].
• Northern blot analysis indicates that the caveolin 3 transcript is 1.6 kb in size and exclusively detectable in muscle tissue [27].
• Neurological examination of all nine subjects from three generations harboring the novel cav-3 mutation showed clear evidence of rippling muscle disease [29].
• Our data indicate that a partial caveolin-3 deficiency should be considered in the differential diagnosis of idiopathic hyperCKemia [9].

References