Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Mutations in smooth muscle α-actin (ACTA2) lead to thoracic aortic aneurysms and dissections

A Corrigendum to this article was published on 01 February 2008

This article has been updated

Abstract

The major function of vascular smooth muscle cells (SMCs) is contraction to regulate blood pressure and flow. SMC contractile force requires cyclic interactions between SMC α-actin (encoded by ACTA2) and the β-myosin heavy chain (encoded by MYH11). Here we show that missense mutations in ACTA2 are responsible for 14% of inherited ascending thoracic aortic aneurysms and dissections (TAAD). Structural analyses and immunofluorescence of actin filaments in SMCs derived from individuals heterozygous for ACTA2 mutations illustrate that these mutations interfere with actin filament assembly and are predicted to decrease SMC contraction. Aortic tissues from affected individuals showed aortic medial degeneration, focal areas of medial SMC hyperplasia and disarray, and stenotic arteries in the vasa vasorum due to medial SMC proliferation. These data, along with the previously reported MYH11 mutations causing familial TAAD1, indicate the importance of SMC contraction in maintaining the structural integrity of the ascending aorta.

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

Access options

Buy this article

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

Figure 1: Identification of ACTA2 as the causative gene responsible for TAAD and livedo reticularis in family TAA327.
Figure 2: Clinical characteristics and familial segregation of ACTA2 mutations in individuals with familial TAAD.
Figure 3: Amino acid substitutions identified in ACTA2 in individuals with familial TAAD.
Figure 4: Impact of ACTA2 mutation on ACTA2 protein structure and function.
Figure 5: Aortic pathology associated with ACTA2 mutations.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

Protein Data Bank

Change history

  • 23 January 2008

    In the version of this article initially published, the affiliation for C S Raman was incorrect. Dr. Raman is affiliated with the Department of Biochemistry and Molecular Biology at the University of Texas Health Science Center, and not with the Structural Biology Center. The error has been corrected in the PDF version of the article.

References

  1. Zhu, L. et al. Mutations in myosin heavy chain 11 cause a syndrome associating thoracic aortic aneurysm/aortic dissection and patent ductus arteriosus. Nat. Genet. 38, 343–349 (2006).

    Article  CAS  Google Scholar 

  2. Vandekerckhove, J. & Weber, K. At least six different actins are expressed in a higher mammal: an analysis based on the amino acid sequence of the amino-terminal tryptic peptide. J. Mol. Biol. 126, 783–802 (1978).

    Article  CAS  Google Scholar 

  3. McHugh, K.M., Crawford, K. & Lessard, J.L. A comprehensive analysis of the developmental and tissue-specific expression of the isoactin multigene family in the rat. Dev. Biol. 148, 442–458 (1991).

    Article  CAS  Google Scholar 

  4. Fatigati, V. & Murphy, R.A. Actin and tropomyosin variants in smooth muscles. Dependence on tissue type. J. Biol. Chem. 259, 14383–14388 (1984).

    CAS  PubMed  Google Scholar 

  5. Schildmeyer, L.A. et al. Impaired vascular contractility and blood pressure homeostasis in the smooth muscle alpha-actin null mouse. FASEB J. 14, 2213–2220 (2000).

    Article  CAS  Google Scholar 

  6. Pannu, H. et al. MYH11 mutations result in a distinct vascular pathology driven by insulin-like growth factor 1 and angiotensin II. Hum. Mol. Genet. 16, 3453–3462 (2007).

    Article  Google Scholar 

  7. Pannu, H., Avidan, N., Tran-Fadulu, V. & Milewicz, D.M. Genetic basis of thoracic aortic aneurysms and dissections: potential relevance to abdominal aortic aneurysms. Ann. NY Acad. Sci. 1085, 242–255 (2006).

    Article  CAS  Google Scholar 

  8. Biddinger, A., Rocklin, M., Coselli, J. & Milewicz, D.M. Familial thoracic aortic dilatations and dissections: a case control study. J. Vasc. Surg. 25, 506–511 (1997).

    Article  CAS  Google Scholar 

  9. Loeys, B.L. et al. Aneurysm syndromes caused by mutations in the TGF-β receptor. N. Engl. J. Med. 355, 788–798 (2006).

    Article  CAS  Google Scholar 

  10. Guo, D. et al. Familial thoracic aortic aneurysms and dissections: genetic heterogeneity with a major locus mapping to 5q13–14. Circulation 103, 2461–2468 (2001).

    Article  CAS  Google Scholar 

  11. Lewis, R.A. & Merin, L.M. Iris flocculi and familial aortic dissection. Arch. Ophthalmol. 113, 1330–1331 (1995).

    Article  CAS  Google Scholar 

  12. Bixler, D. & Antley, R.M. Familial aortic dissection with iris anomalies—a new connective tissue disease syndrome? Birth Defects Orig. Artic. Ser. 12, 229–234 (1976).

    CAS  PubMed  Google Scholar 

  13. Finkbohner, R., Johnston, D., Crawford, E.S., Coselli, J. & Milewicz, D.M. Marfan syndrome. Long-term survival and complications after aortic aneurysm repair. Circulation 91, 728–733 (1995).

    Article  CAS  Google Scholar 

  14. Dominguez, R. Actin-binding proteins—a unifying hypothesis. Trends Biochem. Sci. 29, 572–578 (2004).

    Article  CAS  Google Scholar 

  15. Klenchin, V.A. et al. Trisoxazole macrolide toxins mimic the binding of actin-capping proteins to actin. Nat. Struct. Biol. 10, 1058–1063 (2003).

    Article  CAS  Google Scholar 

  16. Page, R., Lindberg, U. & Schutt, C.E. Domain motions in actin. J. Mol. Biol. 280, 463–474 (1998).

    Article  CAS  Google Scholar 

  17. Small, J.V. & Gimona, M. The cytoskeleton of the vertebrate smooth muscle cell. Acta Physiol. Scand. 164, 341–348 (1998).

    Article  CAS  Google Scholar 

  18. Nowak, K.J. et al. Mutations in the skeletal muscle α-actin gene in patients with actin myopathy and nemaline myopathy. Nat. Genet. 23, 208–212 (1999).

    Article  CAS  Google Scholar 

  19. Sparrow, J.C. et al. Muscle disease caused by mutations in the skeletal muscle alpha-actin gene (ACTA1). Neuromuscul. Disord. 13, 519–531 (2003).

    Article  Google Scholar 

  20. Ahmad, F., Seidman, J.G. & Seidman, C.E. The genetic basis for cardiac remodeling. Annu. Rev. Genomics Hum. Genet. 6, 185–216 (2005).

    Article  CAS  Google Scholar 

  21. Nowak, K.J. et al. Nemaline myopathy caused by absence of alpha-skeletal muscle actin. Ann. Neurol. 61, 175–184 (2007).

    Article  CAS  Google Scholar 

  22. Crawford, K. et al. Mice lacking skeletal muscle actin show reduced muscle strength and growth deficits and die during the neonatal period. Mol. Cell. Biol. 22, 5887–5896 (2002).

    Article  CAS  Google Scholar 

  23. Pannu, H. et al. Mutations in transforming growth factor-beta receptor type II cause familial thoracic aortic aneurysms and dissections. Circulation 112, 513–520 (2005).

    Article  CAS  Google Scholar 

  24. Geisterfer-Lowrance, A.A. et al. A molecular basis for familial hypertrophic cardiomyopathy: a beta cardiac myosin heavy chain gene missense mutation. Cell 62, 999–1006 (1990).

    Article  CAS  Google Scholar 

  25. Tardiff, J.C. Sarcomeric proteins and familial hypertrophic cardiomyopathy: linking mutations in structural proteins to complex cardiovascular phenotypes. Heart Fail. Rev. 10, 237–248 (2005).

    Article  CAS  Google Scholar 

  26. Gudbjartsson, D.F., Jonasson, K., Frigge, M.L. & Kong, A. Allegro, a new computer program for multipoint linkage analysis. Nat. Genet. 25, 12–13 (2000).

    Article  CAS  Google Scholar 

  27. He, R. et al. Characterization of the inflammatory and apoptotic cells in the aortas of patients with ascending thoracic aortic aneurysms and dissections. J. Thorac. Cardiovasc. Surg. 131, 671–678 (2006).

    Article  Google Scholar 

  28. Poindexter, B.J. Immunofluorescence deconvolution microscopy and image reconstruction of human defensins in normal and burned skin. J. Burns Wounds 4, e7 (2005).

    PubMed  PubMed Central  Google Scholar 

  29. Holmes, K.C., Angert, I., Kull, F.J., Jahn, W. & Schroder, R.R. Electron cryo-microscopy shows how strong binding of myosin to actin releases nucleotide. Nature 425, 423–427 (2003).

    Article  CAS  Google Scholar 

  30. Otterbein, L.R., Graceffa, P. & Dominguez, R. The crystal structure of uncomplexed actin in the ADP state. Science 293, 708–711 (2001).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors are grateful to the families and their physicians involved in this study, to S. Veeraraghavan for help generating the structure panels and to C. Akers for excellent graphic assistance. The following sources provided funding for these studies: RO1 HL62594 (D.M.M.), P50HL083794-01 (D.M.M.), UL1 RR024148 (CTSA), and TexGen Foundation. D.M.M. is a Doris Duke Distinguished Clinical Scientist. C.S.R. is a Pew Scholar. R.A.L. is a Senior Scientific Investigator of Research to Prevent Blindness, New York, New York.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Dianna M Milewicz.

Supplementary information

Supplementary Text and Figures

Supplementary Note, Reference List, Supplementary Tables 1–5, Supplementary Figures 1–3 (PDF 852 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Guo, DC., Pannu, H., Tran-Fadulu, V. et al. Mutations in smooth muscle α-actin (ACTA2) lead to thoracic aortic aneurysms and dissections. Nat Genet 39, 1488–1493 (2007). https://doi.org/10.1038/ng.2007.6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.2007.6

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing