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.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Craig, R. in Myology (eds Engel, A.G. & Franzini-Armstrong, C.) 134–175 (McGraw-Hill, New York, 1994).
Taylor, A., Erba, H., Muscat, G. & Kedes, L. Nucleotide sequence and expression of the human skeletal α-actin gene: evolution of functional regulatory domains. Genomics 3, 323–336 (1988).
Olson, T.M., Michels, V.V., Thibodeau, S.N., Tai, Y.-S. & Keating, M.T. Actin mutations in dilated cardiomyopathy, a heritable form of heart failure. Science 280, 750–752 (1998).
Mogensen, J. et al. α-cardiac actin is a novel disease gene in familial hypertrophic cardiomyopathy. J. Clin. Invest. 103, R39–R43 (1999).
Geisterfer-Lowrance, A.A.T. et al. A molecular basis for familial hypertrophic cardiomyopathy: a β-cardiac myosin heavy chain gene missense mutation. Cell 62, 999–1006 (1990).
Well, D. et al. Defective myosin VIIa gene responsible for Usher syndrome type 1b. Nature 374, 60–61 (1995).
Goebel, H.H., Anderson, J.R., Hubner, C., Oexle, K. & Warlo, I. Congenital myopathy with excess of thin myofilaments. Neuromuscul. Disord. 7, 160–168 (1997).
Wallgren-Pettersson, C. & Laing, N.G. in Inherited Neuromuscular Disorders: Clinical and Molecular Genetics (ed. Emery, A.E.H.) 247–262 (John Wiley and Sons, Chichester, 1998).
Sheterline, P., Clayton, J. & Sparrow, J.C. Actin 1–272 (Oxford University Press, Oxford, 1999).
Goldfarb, L.G. et al. Missense mutations in desmin associated with familial cardiac and skeletal myopathy. Nature Genet. 19, 402–403 (1998).
Akkari, P.A. et al. Assignment of the human skeletal muscle α actin gene (ACTA1) to 1q42 by fluorescence in situ hybridisation. Cytogenet. Cell. Genet. 65, 265–267 (1994).
North, K.N. et al. Nemaline myopathy: current concepts. J. Med. Genet. 34, 705–713 (1997).
Roa, B.B. et al. Charcot-Marie-Tooth disease type-1A—association with a spontaneous point mutation in the PMP22 gene. N. Engl. J. Med. 329, 96–101 (1993).
Wertman, K.F., Drubin, D.G. & Botstein, D. Systematic mutational analysis of the yeast ACT1 gene. Genetics 132, 337–350 (1992).
Drummond, D.R., Hennessey, E.S. & Sparrow, J.C. Characterisations of missense mutations in the Act88F gene of Drosophila melanogaster. Mol. Gen. Genet. 226, 70–80 (1991).
Sakai, Y., Okamato, H., Mogami, K., Yamada, T. & Hotta, Y. Actin with tumor-related mutation is antimorphic in Drosophila muscle: two distinct modes of myofibrillar disruption by antimorphic alleles. J. Biochem. 107, 499–505 (1990).
Drummond, D., Hennessey, E.S. & Sparrow, J.C. The binding of mutant actins to profilin, ATP and DNase I. Eur. J. Biochem. 209, 171–179 (1992).
Hegyi, G., Premecz, G., Sain, B. & Muhlrad, A. Selective carbethoxylation of the histidine residues of actin by diethylpyrocarbonate. Eur. J. Biochem. 44, 7–12 (1974).
Wallgren-Pettersson, C. Congenital nemaline myopathy: a clinical follow-up study of twelve patients. J. Neurol. Sci. 89, 1–14 (1989).
Lefebvre, S. et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell 80, 155–165 (1995).
Dietzen, C.J., D'Auria, R., Fesenmeier, J. & Oh, S.J. Electromyography in benign congenital myopathies. Muscle Nerve 16, 328 (1993).
Laing, N.G. et al. A mutation in the α-tropomyosin gene TPM3 associated with autosomal dominant nemaline myopathy. Nature Genet. 9, 75–79 (1995).
Tan, P. et al. Homozygosity for a nonsense mutation in the α-tropomyosin gene TPM3 in a patient with severe nemaline myopathy. Neuromuscul. Disord. 7, 427–428 (1997).
Pelin, K. et al. Mutations in the nebulin gene associated with autosomal recessive nemaline myopathy. Proc. Natl Acad. Sci. USA 96, 2305–2310 (1999).
Lammens, M. et al. Fetal akinesia sequence caused by nemaline myopathy. Neuropediatrics 28, 116–119 (1997).
Laing, N.G. Inherited disorders of contractile proteins in skeletal and cardiac muscle. Curr. Opin. Neurol. 8, 391–396 (1995).
Bassam, B.J., Caetano-Anolles, G. & Gresshoff, P.M. Fast and sensitive silver staining of DNA in polyacrylamide gels. Anal. Biochem. 196, 80–83 (1991).
Mendelson, R. & Morris, E.P. The structure of the acto-myosin subfragment complex: results of searches using data from electron microscopy and X-ray crystallography. Proc. Natl Acad. Sci. USA 94, 8533–8538 (1997).
Kabsch, W., Mannherz, H.G., Suck, D., Pai, E.F. & Holmes, K.C. Atomic structure of the actin:DNase I complex. Nature 347, 37–44 (1990).
Jones, T.A., Zou, J.Y., Cowan, S.W. & Kjeldgaard, M. Improved methods for building protein models in electron density maps and the location of errors in these models. Acta Cryst. A 47, 110–119 (1991).
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.
About this article
Seminars in Pediatric Neurology (2019)
Seminars in Pediatric Neurology (2019)
Neuromuscular Disorders (2019)
Journal of Muscle Research and Cell Motility (2019)
Human Molecular Genetics (2019)