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)


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.


Hypertrophic Cardiomyopathy Myosin Head Regulatory Light Chain Motility Assay Essential Light Chain 
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Copyright information

© Plenum Press, New York 1998

Authors and Affiliations

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

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