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Link to original content: https://doi.org/10.1038/ng.2007.6
Mutations in smooth muscle α-actin (ACTA2) lead to thoracic aortic aneurysms and dissections | Nature Genetics
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Mutations in smooth muscle α-actin (ACTA2) lead to thoracic aortic aneurysms and dissections

Nature Genetics volume 39, pages 1488–1493 (2007)Cite this article

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.

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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.

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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.

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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

  1. Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, 77030, Texas, USA

    Dong-Chuan Guo, Hariyadarshi Pannu, Van Tran-Fadulu, Christina L Papke, Nili Avidan, Scott Bourgeois, Poyee P Tung, Chul Ahn & Dianna M Milewicz

  2. Department of Epidemiology, University of Texas M.D. Anderson Cancer Center, Houston, 77030, Texas, USA

    Robert K Yu & Sanjay S Shete

  3. Department of Cardiothoracic and Vascular Surgery, University of Texas Health Science Center at Houston, Houston, 77030, Texas, USA

    Anthony L Estrera & Hazim J Safi

  4. Department of Internal Medicine, Ohio State University, Columbus, 43210, Ohio, USA

    Elizabeth Sparks

  5. Clinical Genetics Research Group, Genetic Health Services Victoria, Royal Children's Hospital, Parkville, 3052, Victoria, Australia

    David Amor

  6. Department of Paediatrics and Child Health, Children's Hospital Westmead, University of Sydney, Sydney, NSW 2006, Australia

    Lesley Ades

  7. Department of Genetics, Northern Ireland Regional Genetics Service, Belfast City Hospital Trust, Belfast, BT97 AB, Northern Ireland, UK

    Vivienne McConnell

  8. Centre for Vision Science, School of Biomedical Sciences, Queens University Belfast, Belfast, BT12 6BA, Northern Ireland, UK

    Colin E Willoughby

  9. Department of Pediatrics, Rhode Island Hospital, Providence, 02903, Rhode Island, USA

    Dianne Abuelo

  10. Department of Pediatrics, University of Iowa Hospitals and Clinics, Iowa City, 52242, Iowa, USA

    Marcia Willing

  11. Department of Ophthalmology, Baylor Eye Consultants, Baylor College of Medicine, Houston, 77030, Texas, USA

    Richard A Lewis

  12. Department of Neurosurgery, Brigham and Women's Hospital and Harvard Medical School, Boston, 02115, Massachusetts, USA

    Dong H Kim

  13. Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, Houston, 77030, Texas, USA

    Steve Scherer

  14. Department of Pathology and Laboratory Medicine, University of Texas Health Center at Houston, Houston, 77030, Texas, USA

    L Maximilian Buja

  15. Department of Biochemistry and Structural Biology Center, University of Texas Health Science Center at Houston, Houston, 77030, Texas, USA

    C S Raman

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Correspondence to Dianna M Milewicz.

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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

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