CAV3

CAV3 is the gene that encodes caveolin-3, a muscle-specific member of the caveolin protein family that forms caveolae in the sarcolemma. Caveolae are small flask-shaped invaginations of the plasma membrane that participate in signal transduction and lipid homeostasis. Caveolin-3 acts as a scaffolding protein, organizing signaling molecules at the muscle cell surface. It is predominantly expressed in skeletal and cardiac muscle, where it contributes to mechanotransduction and regulation of signaling pathways such as nitric oxide signaling and insulin signaling. The protein is about 151 amino acids long and contains a caveolin scaffolding domain; it inserts into the plasma membrane as a hairpin, with the N- and C-terminal regions in the cytosol and forming caveolae together with cavin proteins.

Mutations in CAV3 lead to a group of disorders known as caveolinopathies, typically inherited in an autosomal dominant pattern. Pathogenic variants cause a spectrum of muscle diseases, including limb-girdle muscular dystrophy type 1C (LGMD-1C), rippling muscle disease, and isolated hyperCKemia. Clinical features vary from mild proximal weakness to episodic muscle cramping and the characteristic rippling of muscles on percussion. Cardiac involvement, including conduction defects and cardiomyopathy, has been reported in some individuals. Diagnosis is based on genetic testing for CAV3 variants, supported by clinical assessment and, in some cases, muscle biopsy showing altered caveolar structure and reduced caveolae density.

Management is supportive and multidisciplinary, focusing on physical therapy, monitoring for cardiomyopathy and arrhythmias, and prevention of secondary complications. There is no disease-modifying cure currently; research continues to elucidate how CAV3 mutations disrupt membrane signaling and caveolae function.