ß-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, 2014 Jul 07.
Article
em En
| MEDLINE
| ID: mdl-24829265
ABSTRACT
RATIONALE Approximately 40% of hypertrophic cardiomyopathy (HCM) is caused by heterozygous missense mutations in ß-cardiac myosin heavy chain (ß-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 ß-cardiac myosin heavy chain Val606Met substitution (VM) that has been identified in several HCM families with wide variation of clinical outcomes, in mice. METHODS ANDRESULTS:
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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Mutação Puntual
/
Cadeias Pesadas de Miosina
/
Substituição de Aminoácidos
/
Mutação de Sentido Incorreto
/
Cardiomiopatia Hipertrófica Familiar
Tipo de estudo:
Diagnostic_studies
/
Etiology_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Circ Res
Ano de publicação:
2014
Tipo de documento:
Article