Skeletal muscle alpha-actin diseases.

Skeletal muscle alpha-actin is the principal protein component of the adult skeletal muscle thin filament. The interaction between skeletal muscle alpha-actin and the various myosin heavy chain proteins in the different muscle fibre types generates the force of muscle contraction. Skeletal muscle alpha-alpha actin is thus of fundamental importance to normal muscle contraction. To date over 140 different disease-causing mutations have been identified in the skeletal muscle alpha-actin gene ACTA1. These mutations are associated with histologically distinct congenital myopathies, including nemaline myopathy, actin myopathy, intranuclear rod myopathy, congenital fibre type disproportion and myopathy with cores. Mutations in ACTA1 are associated with a wide range of clinical severity although the majority of patients tend to have severe congenital-onset disease. Most of the patients have de novo dominant mutations not present in either parent. However mild ACTA1 disease may be dominantly inherited and there are also recessive mutations. The recessive mutations are either genetic or functional null mutations. Patients with no skeletal actin retain cardiac actin, the fetal isoform of actin in skeletal muscle. Information from the clinic suggests that exercise and L-tyrosine may benefit some patients and that in the future decreasing the proportion of mutant actin may ameliorate the disease in some patients.