β-Myosin Heavy Chain Variant Val606Met Causes Very Mild Hypertrophic Cardiomyopathy in Mice, but Exacerbates HCM Phenotypes in Mice Carrying Other HCM Mutations

• Published in: Circulation research Vol. 115; no. 2; pp. 227 - 237
• Main Authors: Blankenburg, Robert, Hackert, Katarzyna, Wurster, Sebastian, Deenen, René, Seidman, J.G., Seidman, Christine E., Lohse, Martin J., Schmitt, Joachim P.
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 07.07.2014
• Subjects: Amino Acid Substitution; Animals; Cardiac Myosins; Cardiomyopathy, Hypertrophic, Familial - diagnostic imaging; Cardiomyopathy, Hypertrophic, Familial - genetics; Cardiomyopathy, Hypertrophic, Familial - pathology; Cyclosporine - toxicity; Disease Models, Animal; Gene Knock-In Techniques; Genotype; Humans; Hypertrophy, Left Ventricular - diagnostic imaging; Hypertrophy, Left Ventricular - genetics; Hypertrophy, Left Ventricular - pathology; Mice; Models, Molecular; Mutation, Missense; Myocardial Contraction; Myosin Heavy Chains - genetics; Myosin Heavy Chains - physiology; Phenotype; Point Mutation; Protein Conformation; Transcription, Genetic; Ultrasonography; Ventricular Myosins - genetics; Ventricular Myosins - physiology; Ventricular Remodeling - genetics; Ventricular Remodeling - physiology; genetics; myocardial contraction; hypertrophy; cardiomyopathies; myosins
• ISSN: 0009-7330; 1524-4571; 1524-4571
• DOI: 10.1161/CIRCRESAHA.115.303178

RATIONALE:Approximately 40% of hypertrophic cardiomyopathy (HCM) is caused by heterozygous missense mutations in β-cardiac myosin heavy chain (β-MHC). Associating disease phenotype with mutation is confounded by extensive background genetic and lifestyle/environmental differences between subjects even from the same family. OBJECTIVE:To characterize disease caused by β-cardiac myosin heavy chain Val606Met substitution (VM) that has been identified in several HCM families with wide variation of clinical outcomes, in mice. METHODS AND RESULTS:Unlike 2 mouse lines bearing the malignant myosin mutations Arg453Cys (RC/+) or Arg719Trp (RW/+), VM/+ mice with an identical inbred genetic background lacked hallmarks of HCM such as left ventricular hypertrophy, disarray of myofibers, and interstitial fibrosis. Even homozygous VM/VM mice were indistinguishable from wild-type animals, whereas RC/RC- and RW/RW-mutant mice died within 9 days after birth. However, hypertrophic effects of the VM mutation were observed both in mice treated with cyclosporine, a known stimulator of the HCM response, and compound VM/RC heterozygous mice, which developed a severe HCM phenotype. In contrast to all heterozygous mutants, both systolic and diastolic function of VM/RC hearts was severely impaired already before the onset of cardiac remodeling. CONCLUSIONS:The VM mutation per se causes mild HCM-related phenotypes; however, in combination with other HCM activators it exacerbates the HCM phenotype. Double-mutant mice are suitable for assessing the severity of benign mutations.