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Circ Res. 2014 Jul 7;115(2):227-37. doi: 10.1161/CIRCRESAHA.115.303178. Epub 2014 May 14.

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

Author information

1
From the Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany (R.B., S.W., M.J.L., J.P.S.); Institute of Pharmacology and Clinical Pharmacology, University Hospital Düsseldorf and Cardiovascular Research Institute Düsseldorf (CARID), Heinrich-Heine-University, Düsseldorf, Germany (K.H., J.P.S.); Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (C.E.S.); Department of Genetics, Harvard Medical School, Boston, MA (J.G.S.); and Bio-Medical Research Center (BMFZ), Heinrich-Heine-University, Düsseldorf, Germany (R.D.).
2
From the Institute of Pharmacology and Toxicology, University of Würzburg, Würzburg, Germany (R.B., S.W., M.J.L., J.P.S.); Institute of Pharmacology and Clinical Pharmacology, University Hospital Düsseldorf and Cardiovascular Research Institute Düsseldorf (CARID), Heinrich-Heine-University, Düsseldorf, Germany (K.H., J.P.S.); Cardiovascular Division, Brigham and Women's Hospital, Boston, MA (C.E.S.); Department of Genetics, Harvard Medical School, Boston, MA (J.G.S.); and Bio-Medical Research Center (BMFZ), Heinrich-Heine-University, Düsseldorf, Germany (R.D.). joachim.schmitt@uni-duesseldorf.de.

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.

KEYWORDS:

cardiomyopathies; genetics; hypertrophy; myocardial contraction; myosins

PMID:
24829265
PMCID:
PMC4086907
DOI:
10.1161/CIRCRESAHA.115.303178
[Indexed for MEDLINE]
Free PMC Article

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