Investigations into the pathobiology of thin-filament myopathies.

Mutations in actin and tropomyosin, identified in patients with myopathic disease have been used in tissue culture models and functional studies with a view to understand how these mutations impact on skeletal muscle structure and function and result in muscle weakness. The likely mode of pathogenesis in these disorders is via a dominant negative effect i.e., the production of 'poison' proteins that interfere with the normal function of the native protein. Tissue culture models and in vitro binding studies highlight the defects of different actin mutants including abnormal folding, aggregation and altered polymerization which would likely impact on skeletal muscle structure and function. The most widely studied mutation in tropomyosin is the M9R substitution identified in a large Australian family with nemaline myopathy. The M9R mutant protein has a reduced affinity for actin, does not bind to tropomodulin in a model peptide and results in reduced sensitivity of isometric force to activating calcium in cardiac myocytes. The pathological consequences of mutations identified in troponin, nebulin, and cofilin are also discussed. Although mutations in alpha-actinin have not been associated with NM, tissue culture models using tagged constructs of different regions of the alpha-actinin gene suggest that this protein plays a role in nemaline body formation.