| First Author | Blankenburg R | Year | 2014 |
| Journal | Circ Res | Volume | 115 |
| Issue | 2 | Pages | 227-37 |
| PubMed ID | 24829265 | Mgi Jnum | J:247162 |
| Mgi Id | MGI:5920620 | Doi | 10.1161/CIRCRESAHA.115.303178 |
| Citation | Blankenburg R, et al. (2014) beta-Myosin heavy chain variant Val606Met causes very mild hypertrophic cardiomyopathy in mice, but exacerbates HCM phenotypes in mice carrying other HCM mutations. Circ Res 115(2):227-37 |
| abstractText | RATIONALE: Approximately 40% of hypertrophic cardiomyopathy (HCM) is caused by heterozygous missense mutations in beta-cardiac myosin heavy chain (beta-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 beta-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. |
