Mutations in the skeletal muscle alpha-actin gene in patients with actin myopathy and nemaline myopathy

Muscle contraction results from the force generated between the thin filame nt protein actin and the thick filament protein myosin, which causes the th ick and thin muscle filaments to slide past each other(1). There are skelet al muscle, cardiac muscle, smooth muscle and non-muscle isoforms of both ac tin and myosin(2). Inherited diseases in humans have been associated with d efects in cardiac actin (dilated cardiomyopathy(3) and hypertrophic cardiom yopathy(4)), cardiac myosin (hypertrophic cardiomyopathy(5)) and non-muscle myosin (deafness(6)). Here we report that mutations in the human skeletal muscle cr-actin gene(2) (ACTA1) are associated with two different muscle di seases, 'congenital myopathy with excess of thin myofilaments' (actin myopa thy(7)) and nemaline myopathy(8). Both diseases are characterized by struct ural abnormalities of the muscle fibres and variable degrees of muscle weak ness. We have identified 15 different missense mutations resulting in 14 di fferent amino acid changes. The missense mutations in ACTA1 are distributed throughout all six coding exons(2), and some involve known functional doma ins of actin(9). Approximately half of the patients died within their first year, but two female patients have survived into their thirties and have c hildren. We identified dominant mutations in all but 1 of 14 families, with the missense mutations being single and heterozygous. The only family show ing dominant inheritance comprised a 33-year-old affected mother and her tw o affected and two unaffected children. In another family, the clinically u naffected father is a somatic mosaic for the mutation seen in both of his a ffected children. We identified recessive mutations in one family in which the two affected siblings had heterozygous mutations in two different exons , one paternally and the other maternally inherited. We also identified de novo mutations in seven sporadic probands for which it was possible to anal yse parental DNA.