MICE EXPRESSING MUTANT MYOSIN HEAVY-CHAINS ARE A MODEL FOR FAMILIAL HYPERTROPHIC CARDIOMYOPATHY

Background: Familial hypertrophic cardiomyopathy (HCM) is an autosomal dominant disease characterized by ventricular hypertrophy, myocellula r disarray, arrhythmias, and sudden death. Mutations in several contra ctile proteins, including cardiac myosin heavy chains, have been descr ibed in families with this disease, leading to the hypothesis that HCM is a disease of the sarcomere. Materials and Methods: A mutation in t he myosin heavy chain (Myh) predicted to interfere strongly with myosi n's binding to actin was designed and used to create an animal model f or HCM. Five independent lines of transgenic mice were produced with c ardiac-specific expression of the mutant Myh. Results: Although the mu tant Myh represents a small proportion (1-12%) of the heart's myosin, the mice exhibit the cardiac histopathology seen in HCM patients. Hist opathology is absent from the atria and primarily restricted to the le ft ventricle. The line exhibiting the highest level of mutant Myh expr ession demonstrates ventricular hypertrophy by 12 weeks of age, but th e further course of the disease is strongly affected by the sex of the animal. Hypertrophy increases with age in female animals while the he arts of male show severe dilation by 8 months of age, in the absence o f increased mass. Conclusions: The low levels of the transgene protein in the presence of the phenotypic features of HCM suggest that the mu tant protein acts as a dominant negative. In addition, the distinct ph enotypes developed by aging male or female transgenic mice suggest tha t extragenic factors strongly influence the development of the disease phenotype.