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

Abstract

Muscle contraction results from the force generated between the thin filament protein actin and the thick filament protein myosin, which causes the thick and thin muscle filaments to slide past each other1. There are skeletal muscle, cardiac muscle, smooth muscle and non-muscle isoforms of both actin and myosin2. Inherited diseases in humans have been associated with defects in cardiac actin (dilated cardiomyopathy3 and hypertrophic cardiomyopathy4), cardiac myosin (hypertrophic cardiomyopathy5) and non-muscle myosin (deafness6). Here we report that mutations in the human skeletal muscle α-actin gene2 (ACTA1) are associated with two different muscle diseases, 'congenital myopathy with excess of thin myofilaments' (actin myopathy7) and nemaline myopathy8. Both diseases are characterized by structural abnormalities of the muscle fibres and variable degrees of muscle weakness. We have identified 15 different missense mutations resulting in 14 different amino acid changes. The missense mutations in ACTA1 are distributed throughout all six coding exons2, and some involve known functional domains of actin9. Approximately half of the patients died within their first year, but two female patients have survived into their thirties and have children. We identified dominant mutations in all but 1 of 14 families, with the missense mutations being single and heterozygous. The only family showing dominant inheritance comprised a 33-year-old affected mother and her two affected and two unaffected children. In another family, the clinically unaffected father is a somatic mosaic for the mutation seen in both of his affected 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 analyse parental DNA.

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Figure 1: Automated sequencing of genomic DNA from patients 1–3 and family 9.
Figure 2
Figure 3: Comparison of actin amino acid sequences in various species and the 15 mutated residues identified in patients with ACTA1 mutations.
Figure 4: Model of F-actin and myosin with actin mutations indicated.

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Acknowledgements

We thank the patients and their families for samples; members of the European Neuromuscular Centre International Consortium on Nemaline Myopathy for collaboration; and C. Huxtable and F. Mastaglia for critical reading of the manuscript. This work was funded by the Australian National Health and Medical Research Council and the Neuromuscular Foundation of Western Australia (K.N., R.L.J., N.G.L.), the Muscular Dystrophy Association and the National Institutes of Health (D.W., A.H.B.), the Deutsche Gesellschaft für Muskelkranke e. V. Freiburg/Germany (H.H.G.), the Association Française contre les Myopathies, the Swedish Cultural Foundation of Finland, the Finska Läkaresällskapet and the Medicinska understödsföreningen Liv och Hälsa (K.P., K.D., C.W.P). We also thank the European Neuromuscular Centre (ENMC) and its main sponsors: Association Francaise contre les Myopathies, Italian Telethon Committee, Muscular Dystrophy Group of Great Britain and Northern Ireland, Vereniging Spierziekten Nederland and Deutsche Gesellschaft für Muskelkranke, Schweizerische Stiftung für die Erforschung der Muskelkrankheiten, Prinses Beatrix Fonds, Verein zur Erforschung von Muskelkrankheiten bei Kindern (Austria) and Muskelsvindfonden (Denmark); and associate members Unione Italiana Lotta alla Distrofia Muscolare and Muscular Dystrophy Association of Finland.

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Correspondence to Nigel G. Laing.

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