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


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.
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.).
Robert
R
Blankenburg
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.).
Katarzyna
K
Hackert
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.).
Sebastian
S
Wurster
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.).
René
R
Deenen
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.).
J G
JG
Seidman
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.).
Christine E
CE
Seidman
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.).
Martin J
MJ
Lohse
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.
Joachim P
JP
Schmitt
D019943:Amino Acid Substitution; D000818:Animals; D024722:Cardiac Myosins; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D016572:Cyclosporine / Q000633:toxicity; D004195:Disease Models, Animal; D055879:Gene Knock-In Techniques; D005838:Genotype; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000000981:diagnostic imaging / Q000235:genetics / Q000473:pathology; D051379:Mice; D008958:Models, Molecular; D020125:Mutation, Missense; D009200:Myocardial Contraction; D018995:Myosin Heavy Chains / Q000235:genetics* / Q000502:physiology; D010641:Phenotype; D017354:Point Mutation; D011487:Protein Conformation; D014158:Transcription, Genetic; D014463:Ultrasonography; D024723:Ventricular Myosins / Q000235:genetics / Q000502:physiology; D020257:Ventricular Remodeling / Q000235:genetics / Q000502:physiology
C501641:MYH7 protein, human; C584019:Myh6 protein, mouse; D016572:Cyclosporine; D024722:Cardiac Myosins; D024723:Ventricular Myosins; D018995:Myosin Heavy Chains
cardiomyopathies; genetics; hypertrophy; myocardial contraction; myosins