β-Myosin heavy chain variant Val606Met causes very mild hypertrophic cardiomyopathy in mice, but exacerbates HCM phenotypes in mice carrying other HCM mutations.

Abstract

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.

• Authors: Robert Blankenburg, Katarzyna Hackert, Sebastian Wurster, René Deenen, J G Seidman, Christine E Seidman, Martin J Lohse, Joachim P Schmitt
• Journal: Circulation research (Circ Res) Vol. 115 Issue 2 Pg. 227-37 (Jul 07 2014) ISSN: 1524-4571 [Electronic] United States
• PMID: 24829265 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 American Heart Association, Inc.

Chemical References

• MYH7 protein, human
• Myh6 protein, mouse
• Cyclosporine
• Cardiac Myosins
• Ventricular Myosins
• Myosin Heavy Chains

Topics

• Amino Acid Substitution
• Animals
• Cardiac Myosins
• Cardiomyopathy, Hypertrophic, Familial (diagnostic imaging, genetics, pathology)
• Cyclosporine (toxicity)
• Disease Models, Animal
• Gene Knock-In Techniques
• Genotype
• Humans
• Hypertrophy, Left Ventricular (diagnostic imaging, genetics, pathology)
• Mice
• Models, Molecular
• Mutation, Missense
• Myocardial Contraction
• Myosin Heavy Chains (genetics, physiology)
• Phenotype
• Point Mutation
• Protein Conformation
• Transcription, Genetic
• Ultrasonography
• Ventricular Myosins (genetics, physiology)
• Ventricular Remodeling (genetics, physiology)