Mutations in the skeletal muscle α-actin gene in patients with actin myopathy and nemaline myopathy (original) (raw)

Nature Genetics volume 23, pages 208–212 (1999)Cite this article

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.

This is a preview of subscription content, access via your institution

Access options

Subscribe to this journal

Receive 12 print issues and online access

$259.00 per year

only $21.58 per issue

Buy this article

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Additional access options:

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

Protein Data Bank

References

  1. Craig, R. in Myology (eds Engel, A.G. & Franzini-Armstrong, C.) 134–175 (McGraw-Hill, New York, 1994).
    Google Scholar
  2. 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).
    Article CAS PubMed Google Scholar
  3. 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).
    Article CAS PubMed Google Scholar
  4. Mogensen, J. et al. α-cardiac actin is a novel disease gene in familial hypertrophic cardiomyopathy. J. Clin. Invest. 103, R39–R43 (1999).
    Article CAS PubMed PubMed Central Google Scholar
  5. 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).
    Article CAS PubMed Google Scholar
  6. Well, D. et al. Defective myosin VIIa gene responsible for Usher syndrome type 1b. Nature 374, 60–61 (1995).
    Article CAS Google Scholar
  7. 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).
    Article CAS PubMed Google Scholar
  8. 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).
    Google Scholar
  9. Sheterline, P., Clayton, J. & Sparrow, J.C. Actin 1–272 (Oxford University Press, Oxford, 1999).
  10. Goldfarb, L.G. et al. Missense mutations in desmin associated with familial cardiac and skeletal myopathy. Nature Genet. 19, 402–403 (1998).
    Article CAS PubMed Google Scholar
  11. 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).
    Article CAS PubMed Google Scholar
  12. North, K.N. et al. Nemaline myopathy: current concepts. J. Med. Genet. 34, 705–713 (1997).
    Article CAS PubMed PubMed Central Google Scholar
  13. 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).
    Article CAS PubMed Google Scholar
  14. Wertman, K.F., Drubin, D.G. & Botstein, D. Systematic mutational analysis of the yeast ACT1 gene. Genetics 132, 337–350 (1992).
    CAS PubMed PubMed Central Google Scholar
  15. 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).
    Article CAS PubMed Google Scholar
  16. 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).
    Article CAS PubMed Google Scholar
  17. 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).
    Article CAS PubMed Google Scholar
  18. 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).
    Article CAS PubMed Google Scholar
  19. Wallgren-Pettersson, C. Congenital nemaline myopathy: a clinical follow-up study of twelve patients. J. Neurol. Sci. 89, 1–14 (1989).
    Article CAS PubMed Google Scholar
  20. Lefebvre, S. et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell 80, 155–165 (1995).
    Article CAS PubMed Google Scholar
  21. Dietzen, C.J., D'Auria, R., Fesenmeier, J. & Oh, S.J. Electromyography in benign congenital myopathies. Muscle Nerve 16, 328 (1993).
    CAS PubMed Google Scholar
  22. 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).
    Article CAS PubMed Google Scholar
  23. 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).
    Article Google Scholar
  24. Pelin, K. et al. Mutations in the nebulin gene associated with autosomal recessive nemaline myopathy. Proc. Natl Acad. Sci. USA 96, 2305–2310 (1999).
    Article CAS PubMed PubMed Central Google Scholar
  25. Lammens, M. et al. Fetal akinesia sequence caused by nemaline myopathy. Neuropediatrics 28, 116–119 (1997).
    Article CAS PubMed Google Scholar
  26. Laing, N.G. Inherited disorders of contractile proteins in skeletal and cardiac muscle. Curr. Opin. Neurol. 8, 391–396 (1995).
    Article CAS PubMed Google Scholar
  27. 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).
    Article CAS PubMed Google Scholar
  28. 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).
    Article CAS PubMed PubMed Central Google Scholar
  29. 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).
    Article CAS PubMed Google Scholar
  30. 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).
    Article Google Scholar

Download references

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.

Author information

Authors and Affiliations

  1. Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Australian Neuromuscular Research Institute, Queen Elizabeth II Medical Centre,, Nedlands, 6009, Western Australia, Australia
    Kristen J. Nowak & Nigel G. Laing
  2. Division of Veterinary and Biomedical Sciences, Murdoch University, Murdoch, Australia
    Kristen J. Nowak
  3. Genetics Division, Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
    Duangrurdee Wattanasirichaigoon, Kathryn J. Swoboda & Alan H. Beggs
  4. Department of Neuropathology, Johannes Gutenberg University, Mainz, Germany
    Hans H. Goebel
  5. Crystallography Centre and Department of Pharmacology, University of Western Australia, Perth, Australia
    Matthew Wilce
  6. The Folkhälsan Institute of Genetics and Department of Medical Genetics, University of Helsinki, Helsinki, Finland
    Katarina Pelin & Kati Donner
  7. Department of Neuropathology, Royal Perth Hospital, Perth, Australia
    Rebecca L. Jacob
  8. Department of Neuropaediatrics, Charite, Humboldt University, Berlin, Germany
    Christoph Hübner & Konrad Oexle
  9. Department of Histopathology, Addenbrooke's Hospital, Cambridge, UK
    Janice R. Anderson
  10. Child Development Centre, Addenbrooke's Hospital,, Cambridge, UK
    Christopher M. Verity
  11. Neurogenetics Research Unit, Royal Alexandra Hospital for Children,, Sydney, Australia
    Kathryn N. North
  12. Neuromuscular Disease and Neurorehabilitation, Texas Scottish Rite Hospital for Children, University of Texas, Southwestern Medical Centre,, Dallas, Texas, USA
    Susan T. Iannaccone
  13. Department of Human Genetics, University of Würzburg, Würzburg, Germany
    Clemens R. Müller
  14. Institute of Medical Genetics, Charite Medical School, Humboldt University,, Berlin, Germany
    Peter Nürnberg
  15. Department of Paediatrics and Neonatal Medicine, Imperial College School of Medicine, Hammersmith Hospital, London, UK
    Francesco Muntoni & Caroline Sewry
  16. Department of Paediatric Neurology, Royal Manchester Children's Hospital, Manchester, UK
    Imelda Hughes
  17. All Children's Hospital and Department of Pediatrics, University of South Florida School of Medicine, Tampa, Florida, USA
    Rebecca Sutphen
  18. All Children's Hospital and Departments of Pathology and Pediatrics, University of South Florida School of Medicine, Tampa, Florida, USA
    Atilano G. Lacson
  19. Service de Maternité Regionale "A. Pinard",, Nancy Cedex, France
    Jaqueline Vigneron
  20. The Folkhälsan Department of Medical Genetics and Department of Medical Genetics, University of Helsinki, Helsinki, Finland
    Carina Wallgren-Pettersson

Authors

  1. Kristen J. Nowak
  2. Duangrurdee Wattanasirichaigoon
  3. Hans H. Goebel
  4. Matthew Wilce
  5. Katarina Pelin
  6. Kati Donner
  7. Rebecca L. Jacob
  8. Christoph Hübner
  9. Konrad Oexle
  10. Janice R. Anderson
  11. Christopher M. Verity
  12. Kathryn N. North
  13. Susan T. Iannaccone
  14. Clemens R. Müller
  15. Peter Nürnberg
  16. Francesco Muntoni
  17. Caroline Sewry
  18. Imelda Hughes
  19. Rebecca Sutphen
  20. Atilano G. Lacson
  21. Kathryn J. Swoboda
  22. Jaqueline Vigneron
  23. Alan H. Beggs
  24. Nigel G. Laing

Corresponding author

Correspondence toNigel G. Laing.

Rights and permissions

About this article

Cite this article

Nowak, K., Wattanasirichaigoon, D., Goebel, H. et al. Mutations in the skeletal muscle α-actin gene in patients with actin myopathy and nemaline myopathy.Nat Genet 23, 208–212 (1999). https://doi.org/10.1038/13837

Download citation

This article is cited by