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Mice expressing mutant myosin heavy chains are a model for familial hypertrophic cardiomyopathy
K L Vikstrom1, S M Factor, L A Leinwand
1Department of Molecular, Cellular, & Developmental Biology, University of Colorado, Boulder 80309-0347, USA.
Insights
This study created a mouse model for familial hypertrophic cardiomyopathy (HCM) using a mutant myosin heavy chain (Myh). The model shows HCM pathology, with distinct sex-specific outcomes, suggesting a dominant-negative effect and extragenic influences.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Animal Models of Disease
Background:
- Familial hypertrophic cardiomyopathy (HCM) is an autosomal dominant disorder.
- It is characterized by ventricular hypertrophy, myocellular disarray, arrhythmias, and sudden death.
- Mutations in contractile proteins, like cardiac myosin heavy chains, suggest HCM is a sarcomere disease.
Purpose of the Study:
- To develop an animal model for HCM.
- To investigate the role of mutant cardiac myosin heavy chain (Myh) in disease development.
- To explore potential sex-specific differences in HCM pathogenesis.
Main Methods:
- Designed a mutation in myosin heavy chain (Myh) to disrupt actin binding.
- Created transgenic mice with cardiac-specific expression of the mutant Myh.
- Analyzed cardiac histopathology and disease progression in five independent mouse lines.
Main Results:
- Transgenic mice exhibited cardiac histopathology consistent with HCM, primarily in the left ventricle.
- The line with highest mutant Myh expression showed ventricular hypertrophy in females and dilation in males.
- Disease progression was significantly influenced by the sex of the animal.
Conclusions:
- The mutant Myh protein acts in a dominant-negative manner, causing HCM phenotypes at low expression levels.
- Distinct phenotypes in aging male and female mice indicate extragenic factors influence HCM.
- This model provides insights into sarcomere dysfunction and sex-based disparities in HCM.
Background:
Familial hypertrophic cardiomyopathy (HCM) is an autosomal dominant disease characterized by ventricular hypertrophy, myocellular disarray, arrhythmias, and sudden death. Mutations in several contractile proteins, including cardiac myosin heavy chains, have been described in families with this disease, leading to the hypothesis that HCM is a disease of the sarcomere.
Materials And Methods:
A mutation in the myosin heavy chain (Myh) predicted to interfere strongly with myosin's binding to actin was designed and used to create an animal model for HCM. Five independent lines of transgenic mice were produced with cardiac-specific expression of the mutant Myh.
Results:
Although the mutant Myh represents a small proportion (1-12%) of the heart's myosin, the mice exhibit the cardiac histopathology seen in HCM patients. Histopathology is absent from the atria and primarily restricted to the left ventricle. The line exhibiting the highest level of mutant Myh expression demonstrates ventricular hypertrophy by 12 weeks of age, but the further course of the disease is strongly affected by the sex of the animal. Hypertrophy increases with age in female animals while the hearts of male show severe dilation by 8 months of age, in the absence of increased mass.
Conclusions:
The low levels of the transgene protein in the presence of the phenotypic features of HCM suggest that the mutant protein acts as a dominant negative. In addition, the distinct phenotypes developed by aging male or female transgenic mice suggest that extragenic factors strongly influence the development of the disease phenotype.