Myopathy mutations in α - skeletal - muscle actin cause a range of molecular defects

Congenital myopathies resulting from mutations in the gene encoding α-skeletal-muscle actin, ACTA1, show various phenotypes that have been divided into three classes based on the morphology observed in patient muscle biopsies (Sparrow et al., 2003). These myopathies have a range of severity, from mild (with long-term survival and only minor muscle weakness), to severe (with lethality shortly after birth). The three classes are: actin myopathy (AM), which is characterized by an excess of thin filamentous inclusions located in what would normally be the myofibrillar filament lattice; intranuclear-rod myopathy (IRM); and nemaline myopathy (NEM), which is characterized by sarcoplasmic deposits containing actin and actin-binding proteins (ABPs) termed 'nemaline bodies' (Sparrow et al., 2003). Although NEM is the most common form of congenital myopathy caused by actin mutations, many patients show more than one histological phenotype in their muscle biopsies, such as the combination of nemaline bodies and intranuclear rods or excess thin filaments. However, Sparrow et al. were able to classify some of the categories of congenital myopathies based on clustering of mutations on the three-dimensional (3D) structure of actin. They could then make predictions