Calpain-3

Calpain-3 is a protein that in humans is encoded by the CAPN3 gene. It is a member of the calpain family, a group of cysteine proteases that are involved in a variety of cellular processes including muscle formation and maintenance. Calpain-3, specifically, plays a critical role in skeletal muscle tissue.

Function

Calpain-3 is a non-lysosomal, calcium-dependent protease that is involved in the remodeling and repair of sarcomeres, which are the basic units of muscle fibers. This protease is essential for muscle integrity and function, participating in the breakdown of damaged or obsolete proteins within muscle cells. Its activity is tightly regulated by calcium levels within the cell, ensuring that proteolysis is initiated only under appropriate physiological conditions.

Clinical Significance

Mutations in the CAPN3 gene are associated with Limb-girdle muscular dystrophy type 2A (LGMD2A), also known as Calpainopathy. This condition is characterized by progressive weakness and wasting of the limb-girdle muscles, which are the muscles around the shoulders and hips. Patients with LGMD2A typically begin to show symptoms in childhood or adolescence. The disease progresses slowly, but it can lead to severe disability over time.

The diagnosis of LGMD2A is confirmed through genetic testing, which can identify mutations in the CAPN3 gene. Muscle biopsy and the measurement of calpain-3 protein activity may also be used to support the diagnosis.

Genetics

The CAPN3 gene is located on the short (p) arm of chromosome 15 at position 15q15.1. It spans over 50 kb and consists of 24 exons. More than 450 mutations in the CAPN3 gene have been identified in individuals with LGMD2A. These mutations can lead to the production of a dysfunctional calpain-3 protein or reduce the amount of the protein, disrupting its normal function in muscle cells.

Treatment and Management

There is currently no cure for LGMD2A, and treatment focuses on managing symptoms and improving quality of life. Physical therapy and occupational therapy can help maintain muscle strength and function. Orthopedic devices such as braces may be used to support weakened muscles. In some cases, surgery may be necessary to correct skeletal deformities resulting from muscle weakness.

Research Directions

Research on calpain-3 is ongoing, with studies aimed at understanding its precise role in muscle physiology and the pathogenesis of LGMD2A. Gene therapy and molecular therapies targeting the CAPN3 gene or calpain-3 protein are being explored as potential treatments for LGMD2A.