Advertisement

The Molecular Biology and Pathophysiology of Hypertrophic Cardiomyopathy Due to Mutations in the Beta Myosin Heavy Chains and the Essential and Regulatory Light Chains

  • Neal D. Epstein
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 453)

Abstract

Hypertrophic cardiomyopathy (HCM) is perhaps the most common cause of inherited sudden death in otherwise healthy young individuals. There are presently seven known genes in which mutations have been shown to cause the disease. The first identified disease gene was beta myosin heavy chain (BMHC). Our laboratory has identified 32 distinct BMHC gene mutations in 62 kindreds after screening representatives of over 400 kindreds. Virtually all but one of approximately 50 known mutations are restricted to the head or head-rod junction region of the molecule. We have used the mutant alleles of the BMHC gene to demonstrate that both mutant message and protein is present in the skeletal muscle of patients with HCM. Muscle biopsies from patients with identified BMHC mutations show abnormal histology. Isolated myosin and skinned fibers from these patients have abnormal mechanical properties. The BMHC gene mutations are clustered in 4 regions of the myosin head. Because one of these regions is adjacent to the ELC, we scanned HCM patient DNA for mutations in either the ELC or RLC. Linkage analysis showed that a unique mutation in the ELC caused a rare phenotype of HCM in one family. Other mutations in either light chain were also associated with the same rare phenotype in other families. Through several lines of reasoning we hypothesized that the light chain mutations interfere with the stretch-activation response of papillary muscle and adjacent ventricular tissue. This property is critical to oscillatory power output of insect flight muscle. We conjectured that this property is also exploited by portions of the heart to increase power output. In order to test this hypothesis we constructed transgenic mouse lines ex-pressing either the human normal or mutant ELC. The cardiac morphology and mechanical properties of the transgenic mouse papillary muscle is now being studied.

Keywords

Hypertrophic Cardiomyopathy Myosin Head Regulatory Light Chain Motility Assay Essential Light Chain 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Maron, B.J. & Epstein, S.E., Am. J. Cardiol. 43, 1242–1244 (1979).PubMedCrossRefGoogle Scholar
  2. 2.
    Geisterfer-Lowrance, A.A.T., Kass, S., Tanigawa, G., Vosberg, H.P., McKenna, W., Seidman, C.E., and Seid-man, J.G. Cell 62, 999–1006 (1990).PubMedCrossRefGoogle Scholar
  3. 3.
    Huxley, A.F. Prog. Biophys. Biophys. Chem. 7, 225–318 (1957)Google Scholar
  4. 4.
    Huxley, H.E. Science 164, 1356–1366 (1969).PubMedCrossRefGoogle Scholar
  5. 5.
    Huxley, A.F. & Simmons, R.M. Nature 233, 533–538 (1972).CrossRefGoogle Scholar
  6. 6.
    Rayment, I. et al. Science 261, 50–58 (1993).PubMedCrossRefGoogle Scholar
  7. 7.
    Rayment, I., Holden, H.M., Sellers, J., Fananapazir, L. & Epstein, N.D. Proc. Natl.Acad. Sci. USA 92, 3864–3868 (1994).CrossRefGoogle Scholar
  8. 8.
    Fananapazir, L., Dalakas, M.C., Cyran, F., Cohn, G. & Epstein, N.D. Proc Natl. Acad. Sci. USA 90, 3993–3997 (1993).PubMedCrossRefGoogle Scholar
  9. 9.
    Cuda, G., Fananapazir, L., Epstein, N.D., and Sellers, J.R. J. of Muscle Res. and Cell Motility 18, 1–9 (1997).CrossRefGoogle Scholar
  10. 10.
    Lankford, E.B., Epstein, N.D., Fananapazir, L. & Sweeney, H.L. J. Clin. Invest. 95, 1409–1414 (1995).PubMedCrossRefGoogle Scholar
  11. 11.
    Poetter, K., Jiang, H., Hassanzadeh, S., Master, S.R., Chang, A., Dalakas, M.C., Rayment, I., Sellers, J.R., Fananapazir, L. & Epstein, N.D. Nature Genetics 13, 63–69 (1996).PubMedCrossRefGoogle Scholar
  12. 12.
    Pringle, J.W.S. Stretch activation of muscle: function and mechanism. Proc. R. Soc. Lond. B. 201, 107–130 (1978).PubMedCrossRefGoogle Scholar
  13. 13.
    Steiger, G.J. in Insect Flight Muscle (ed. Tregear, R.T.) 221–268 (North Holland, Amsterdam, 1977).Google Scholar
  14. 14.
    Cuda, G., Fananapazir, L., Zhu, W.-Z., Sellers, J. & Epstein, N.D. J. Clin. Invest. 91, 2861–2865 (1993).PubMedCrossRefGoogle Scholar
  15. 15.
    Spudich, J.A. Nature 372, 515–518 (1994).PubMedCrossRefGoogle Scholar
  16. 16.
    Whittaker, M. et al. Nature 378, 748–751 (1995).PubMedCrossRefGoogle Scholar
  17. 17.
    Irving, M. et al. Nature 375, 688–691 (1995).PubMedCrossRefGoogle Scholar
  18. 18.
    VanBuren, P., Waller, G.S., Harris, D.E., Trybus, K.M., Warshaw, D.M. & Lowey, S. Proc.Natl. Acad. Sci. USA 91, 12403–12407 (1994).CrossRefGoogle Scholar
  19. 19.
    Adhikari, B. Hideg, K. Fajer, P.G. Proc.Natl. Acad. Sci. USA 94, 9643–9647 (1997).PubMedCrossRefGoogle Scholar
  20. 20.
    Hill, T.L. Free Energy transduction in Biology (Academic Press, N.Y., 1977)Google Scholar

Copyright information

© Plenum Press, New York 1998

Authors and Affiliations

  • Neal D. Epstein
    • 1
  1. 1.Cardiology BranchNHLBI, NIHBethesdaUSA

Personalised recommendations