• Robert Blankenburg, Katarzyna Hackert, Sebastian Wurster, René Deenen, J G Seidman, Christine E Seidman, Martin J Lohse, and Joachim P Schmitt.
• 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.).
• Circ. Res. 2014 Jul 7;115(2):227-37.

RationaleApproximately 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.ObjectiveTo 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 ResultsUnlike 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.ConclusionsThe 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.© 2014 American Heart Association, Inc.

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