Human homozygous R403W mutant cardiac myosin presents disproportionate enhancement of mechanical and enzymatic properties.

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%; P<0.001). Mutant myosin exhibited a large increase in maximal actin-activated ATPase activity (+114%; P<0.05) and Km for actin (+87%; P<0.05) 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.

• Authors: Dagmar I Keller, Catherine Coirault, Thomas Rau, Theary Cheav, Michael Weyand, Kerstin Amann, Yves Lecarpentier, Pascale Richard, Thomas Eschenhagen, Lucie Carrier
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 36 Issue 3 Pg. 355-62 (Mar 2004) ISSN: 0022-2828 [Print] England
• PMID: 15010274 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carrier Proteins
• Molecular Motor Proteins
• myosin-binding protein C
• Adenosine Triphosphate
• Adenosine Triphosphatases
• Myosin Heavy Chains

Topics

• Actin Cytoskeleton (metabolism)
• Adenosine Triphosphatases (chemistry)
• Adenosine Triphosphate (metabolism)
• Adolescent
• Adult
• Animals
• Base Sequence
• Cardiomyopathy, Hypertrophic, Familial (enzymology, genetics, pathology)
• Carrier Proteins (genetics)
• Humans
• Molecular Motor Proteins (genetics)
• Molecular Sequence Data
• Myosin Heavy Chains (chemistry, genetics)
• Point Mutation (genetics)
• Rabbits
• Sequence Analysis, DNA