1. Human homozygous R403W mutant cardiac myosin presents disproportionate enhancement of mechanical and enzymatic properties
- Author
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Yves Lecarpentier, Kerstin Amann, Dagmar I. Keller, Pascale Richard, Michael Weyand, Thomas Rau, Thomas Eschenhagen, Lucie Carrier, Catherine Coirault, and Theary Cheav
- Subjects
Adult ,Adolescent ,Molecular Sequence Data ,Mutant ,macromolecular substances ,Biology ,Muscle hypertrophy ,Adenosine Triphosphate ,Myosin ,Cardiomyopathy, Hypertrophic, Familial ,medicine ,Animals ,Humans ,Point Mutation ,Myocyte ,Molecular Biology ,Actin ,Adenosine Triphosphatases ,Genetics ,Base Sequence ,Myosin Heavy Chains ,Molecular Motor Proteins ,Hypertrophic cardiomyopathy ,Sequence Analysis, DNA ,medicine.disease ,Molecular biology ,Actin Cytoskeleton ,MYH7 ,Rabbits ,MYH6 ,Carrier Proteins ,Cardiology and Cardiovascular Medicine - Abstract
Familial hypertrophic cardiomyopathy (FHC) is associated with mutations in 11 genes encoding sarcomeric proteins. Most families present mutations in MYBPC3 and MYH7 encoding cardiac myosin-binding protein C and beta-myosin heavy chain. The consequences of MYH7 mutations have been extensively studied at the molecular level, but controversial results have been obtained with either reduced or augmented myosin motor function depending on the type or homogeneity of myosin studied. In the present study, we took advantage of the accessibility to an explanted heart to analyze for the first time the properties of human homozygous mutant myosin. The patient exhibited eccentric hypertrophy with severely impaired ejection fraction leading to heart transplantation, and carries a homozygous mutation in MYH7 (R403W) and a heterozygous variant in MYBPC3 (V896M). In situ analysis of the left ventricular tissue showed myocyte disarray and hypertrophy plus interstitial fibrosis. In vitro motility assays showed a small, but significant increase in sliding velocity of fluorescent-labeled actin filaments over human mutant cardiac myosin-coated surface compared to control (+18%; P0.001). Mutant myosin exhibited a large increase in maximal actin-activated ATPase activity (+114%; P0.05) and Km for actin (+87%; P0.05) when compared to control. These data show disproportionate enhancement of mechanical and enzymatic properties of human mutant myosin. This suggests inefficient ATP utilization and reduced mechanical efficiency in the myocardial tissue of the patient, which could play an important role in the development of FHC phenotype.
- Published
- 2004